Synthesis and biological investigations of 3β-aminotropane arylamide derivatives with atypical antipsychotic profile

Article abstract of DOI:10.1007/s00044-018-2203-z

This work is a continuation of our previous research, concentrating this time on lead structure modification to increase the 5-HT_1A receptor affinity and water solubility of designed compounds. Therefore, the compounds synthesised within the present project included structural analogues of 3β-acylamine derivatives of tropane with the introduction of a methyl substituent in the benzyl ring and a 2-quinoline, 3-quinoline, or 6-quinoline moiety. A series of novel 3β-aminotropane derivatives was evaluated for their affinity for 5-HT_1A, 5-HT_2A, and D₂ receptors, which allowed for the identification of compounds 12e, 12i, and 19a as ligands with highest affinity for the tested receptors; they were then subjected to further evaluation in preliminary in vivo studies. Selected compounds 12i and 19a displayed antipsychotic properties in the d-amphetamine-induced and MK-801-induced hyperlocomotor activity test in mice. Moreover, compound 19a showed significant antidepressant-like activity in the forced swim test in mice.

Full text of DOI:10.1007/s00044-018-2203-z

MEDICINAL
CHEMISTRY
RESEARCH
Medicinal Chemistry Research (2018) 27:1906–1928
https://doi.org/10.1007/s00044-018-2203-z
ORIGINAL RESEARCH
Synthesis and biological investigations of 3β-aminotropane
arylamide derivatives with atypical antipsychotic profile
Jacek Stefanowicz1 Tomasz Słowiński1 Martyna Z. Wróbel1 Grzegorz Ślifirski1 Maciej Dawidowski1
●
●
●
●
●
Zdzisława Stefanowicz2 Magdalena Jastrzębska-Więsek3 Anna Partyka3 Anna Wesołowska3 Jadwiga Turło1
●
●
●
●
Received: 13 March 2018 / Accepted: 2 June 2018 / Published online: 22 June 2018
© The Author(s) 2018
Abstract
This work is a continuation of our previous research, concentrating this time on lead structure modification to increase the 5-
HT1A receptor affinity and water solubility of designed compounds. Therefore, the compounds synthesised within the
present project included structural analogues of 3β-acylamine derivatives of tropane with the introduction of a methyl
substituent in the benzyl ring and a 2-quinoline, 3-quinoline, or 6-quinoline moiety. A series of novel 3β-aminotropane
derivatives was evaluated for their affinity for 5-HT1A, 5-HT2A, and D2 receptors, which allowed for the identification of
compounds 12e, 12i, and 19a as ligands with highest affinity for the tested receptors; they were then subjected to further
evaluation in preliminary in vivo studies. Selected compounds 12i and 19a displayed antipsychotic properties in the d-
amphetamine-induced and MK-801-induced hyperlocomotor activity test in mice. Moreover, compound 19a showed
significant antidepressant-like activity in the forced swim test in mice.
●
●
●
Keywords Atypical antipsychotics 3β-aminotropane derivatives 5-HT1A, 5-HT2A, D2 Dopamine receptor ligands
Introduction
correlates with the strength of affinity for these receptors.
Dosage has not been shown to correlate with affinity for
non-D2 receptors (Rzewuska 2009). First-generation, or
typical, antipsychotics, such as chlorpromazine or haloper-
idol are antagonists of D2 receptors, while second-genera-
tion, or atypical, antipsychotics (clozapine, olanzapine,
risperidone) are described as antagonists of 5-HT2A/D2, the
antagonistic effect on 5-HT2A receptors being greater than
that against D2 receptors (Meltzer 2013; Möller et al. 2015).
The three newest antipsychotic drugs listed above are
characterised as being partial agonists of D2 receptors
(Citrome 2015; Stahl 2015, 2016; Frankel and Schwartz
2017).
The drug files for typical and atypical, including the latest,
antipsychotics (aripiprazole, brexpiprazole, cariprazine) on
FDA’s Accessdata drug data base website contain the
information that their mechanism of action is unknown
(FDA 2008a, 2013b, 2014c, 2014d, 2015e, 2015f, 2015g,
2015h). However, in vitro studies show that all anti-
psychotic drugs bind to D2 receptors and the dosage
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s00044-018-2203-z) contains supplementary
material, which is available to authorised users.
These findings indicate that inhibition of dopaminergic
transmission appears to be fundamentally important in the
treatment of symptoms of schizophrenia.
* Martyna Z. Wróbel
martyna.wrobel@wum.edu.pl
martynawrobel.wum@gmail.com
The dopaminergic hypothesis also furnishes the best
known explanation of the relation between neurochemical
factors and the clinical manifestations of schizophrenia.
Historically, the hypothesis was made increasingly more
precise in three stages (Howes and Kapur 2009). The first
concept (I), finally formulated in the 1970’s, was called the
dopamine receptor hypothesis. The main focus was on
dopaminergic hyperactivity, the control of which via
blocking dopamine receptors was supposed to provide
1
Department of Drug Technology and Pharmaceutical
Biotechnology, Faculty of Pharmacy, Medical University of
Warsaw, 1 Banacha Street, 02-097 Warsaw, Poland
2
Department of Inorganic and Analytical Chemistry, Faculty of
Pharmacy, Medical University of Warsaw, 1 Banacha Street, 02-
097 Warsaw, Poland
3
Department of Clinical Pharmacy, Jagiellonian University Medical
College, 9 Medyczna Street, 30-688 Cracow, Poland

Medicinal Chemistry Research (2018) 27:1906–1928
1907
effective therapy (Creese et al. 1976). Thus, it was a very
general idea that did not account for differences between
individual dimensions of schizophrenia (e.g., classification
of symptoms), risk factors or the relation between different
levels of dopamine noted in various areas within the CNS
and the clinical expression of symptoms (Snyder 1976). The
second concept (II) of 1991 already considered differences
in dopaminergic activity between individual regions of the
cerebrum, also with regard to various subtypes of the
receptor (D1 vs. D2) (Davis et al. 1991). The main
assumption of that concept was frontal dopaminergic
hypoactivity resulting in striatal dopaminergic hyper-
activity. The negative symptoms of schizophrenia were
explained in terms of inadequate dopaminergic transmission
in the frontal cortical areas and the positive symptoms were
attributed to increased dopaminergic transmission in sub-
cortical nuclei. This concept also had its weaknesses such as
the absence of direct evidence at that time for low cortical
dopamine levels, ignoring the fact that cortical phenomena
are more complex than “hypofrontality” alone, lack of a
model linking those abnormalities with clinical phenomena
(e.g., the link between dopaminergic hyperactivity and
delusions) or failure to include the aetiology of dopami-
nergic imbalance in schizophrenia (Davis et al. 1991; Tsoi
et al. 2008; Howes and Kapur 2009). The third concept (III)
(2009) is based on four core assumptions:
antipsychotics do not treat the underlying abnormalities.
Antipsychotics influences the postsynaptic effects of
abnormal dopamine release, while the actual problem occurs
at an earlier (presynaptic) stage (second assumption). The
third and fourth assumptions address psychosis as a salience
syndrome. Dopaminergic dysregulation in schizophrenia is
viewed here as an extremely significant, but not the only,
component contributing to onset of clinical symptoms.
Changes in many neuronal and neurotransmitter systems,
combined with other biological and environmental factors,
lead to dopaminergic hyperactivity in the striatum. It can be
said that dopaminergic dysregulation that has reached a
certain level of severity, combined with corresponding
clinical phenomena, such as delusions and hallucinations,
leads to a diagnosis of psychosis and/or schizophrenia.
Other neurotransmitters should also be considered
besides dopamine (Howes and Kapur 2009). In this regard,
significant interaction is hypothesised to take place between
dopaminergic and serotonergic pathways. Influence on
serotonergic receptors may be the underlying cause of
cognitive disturbances and negative symptoms seen in
psychoses and mood disorders (Meltzer and Massey 2011;
Sumiyoshi et al. 2014). Clozapine, the pioneering atypical
antipsychotic with known efficacy against negative symp-
toms, acts as a 5-HT2A receptor antagonist (Meltzer and
Massey 2011). It demonstrates a much lower affinity for the
D2 receptor compared to classical neuroleptics. Similar
properties are exhibited by other atypical antipsychotics,
namely olanzapine, risperidone, zotepine, sertindole, que-
tiapine or ziprasidone, whose discovery was greatly influ-
enced by Meltzer et al.’s hypothesis that compounds of this
class should be characterised by a particular 5-HT2A/D2 pKi
ratio (Meltzer’s Index) (Meltzer et al. 1989; Meltzer and
Huang 2008; Meltzer and Massey 2011). Cortical 5-HT2A
receptors may play a key role in the development of psy-
choses via modulating intracortical and cortico-subcortical
glutamatergic transmission (Meltzer and Huang 2008).
Several new antipsychotic and antidepressant medications
(cariprazine, brexpiprazole, quetiapine) reduce the severity
of negative symptoms also partly via 5-HT1A receptors,
while producing milder extrapyramidal symptoms (New-
man-Tancredi and Albert 2012; Sumiyoshi et al. 2014;
Haleem 2015). Taking advantage of action at this
receptor may positively influence patients’ motivation
(Neves et al. 2010).
●
risk factors for schizophrenia are linked with one
another and result in dysregulation of dopaminergic
neurotransmission. Regardless of the cause, it is this
dysregulation that is the starting point for the develop-
ment of psychosis in schizophrenia;
●
dysregulation of dopaminergic transmission occurs at
the level of presynaptic control rather than, as was
previously believed, postsynaptic D2 receptors;
●
dopaminergic dysregulation may be associated with
psychosis rather than schizophrenia, and, for most of its
duration, with susceptibility to psychosis. An indivi-
dual’s diagnosis may be related to the type of factors
that have produced the psychosis and to socio-cultural
conditions;
●
dopamine dysregulation may alter an individual’s
assessment of stimuli, perhaps as a result of impaired
salience (Howes and Kapur 2009).
The first assumption refers to factors associated with the
prenatal period and early childhood, the environment and
genetic determinants. It assumes that these are the factors
that dopaminergic dysfunction, an abnormality consisting in
increased striatal levels of dopamine, is associated with
(Haleem 2015; Howes et al. 2017). This assumption changes
the approach to antipsychotic therapy and is based on
Our previous publications have described the synthesis
and biological activity studies of new derivatives of 3β-
aminotropane (Słowiński et al. 2011, 2013; Stefanowicz
et al. 2016). Some of these derivatives demonstrate high
activity at the D2, 5HT1A, and 5-HT2A receptors (Fig. 1).
The binding affinity profiles of these structures are
similar to those of the recognised atypical antipsychotics
observations
indicating
that
currently
available
clozapine (Ki [nM]=D2 = 130; 5-HT1A = 140; 5-HT2A =

1908
Medicinal Chemistry Research (2018) 27:1906–1928
8.9) and quetiapine (Ki [nM] = D2 = 180; 5-HT1A = 230; 5-
HT2A = 220) (Schmidt et al. 2001).
The additional nitrogen atom is placed in a naphthalene
system, producing quinoline and isoquinoline derivatives,
or/and in a phenyl ring, producing pyridine derivatives, or
in the form of an amine moiety, as a substituent of the
phenyl ring (Fig. 2). The linking position for the quinoline
and isoquinoline systems remains the same as in 2-
naphthalene derivatives as this configuration generates
much better affinity for the D2, 5-HT1A, and 5-HT2A
receptors than in 1-naphthalene analogues (Słowiński et al.
2011; Zajdel et al. 2012). We are proceeding with synthesis
of equatorial isomers (β) only as they possess much
better affinity for the receptors of interest than their axial
(α) analogues (Słowiński et al. 2011; Stefanowicz et al.
2016).
The aim of our work is to continue the search for new
compounds with antipsychotic potential in this group of
derivatives. We decided to synthesise and analyse analo-
gues of the above structures containing an additional
nitrogen atom in the molecule (Fig. 2). The addition of a
nitrogen atom will certainly influence their biological
activity and will make it possible to study electron effects
on binding affinity for selected molecular targets, while also
improving water solubility of salts of these new compounds
as salts of the exemplary structures (Fig. 1) are characterised
by very poor solubility.
N
Material and methods
Chemistry
NH
H
R
O
R = -H
Ki [nM] = D2=82.4; 5-HT1A=303.8; 5-HT2A=2.5
Ki [nM] = D2=3.3; 5-HT1A=182.0; 5-HT2A=231.0
Ki [nM] = D2=11.6; 5-HT1A=199.5; 5-HT2A=105.7
General remarks
R = -CH3
R = -Br
All solvents and raw materials were purchased from com-
mercial sources. Column chromatography was carried out
using a Merck Silica gel 60 A (63–200 µm) column as the
Fig. 1 Arylamide derivatives of 3β-aminotropane
Fig. 2 Rationale of the planned structural modifications

Medicinal Chemistry Research (2018) 27:1906–1928
1909
stationary phase and chloroform:methanol (9:1 v/v) as elu-
ent. Melting points were determined on an Electrothermal
9100 apparatus with open capillary tubes and were uncor-
rected. IR spectra were obtained using a Shimadzu FTIR-
8300 spectrometer. NMR spectra were recorded on a Varian
Inova 500 (500 MHz) spectrometer. Chemical shifts (δ)
were expressed in parts per million (ppm) relative to tetra-
methylsilane used as the internal reference. The following
abbreviations are used to describe peak patterns when
appropriate: s (singlet), bs (broad singlet), d (doublet), dd
(double doublet), t (triplet), td (triple doublet), pt (pseudo
triplet), 4d (quartet of doublets), m (multiplet), q (quartet),
qu (quintet), * (overlapping signals). Coupling constants (J)
are in hertz (Hz). ESI-HRMS spectra were obtained on an
LCT TOF (Micromass) instrument. Intermediate 8 and 9
(Scheme 1) was obtained following the protocol in Ref.
(Słowiński et al. 2011; Dostert et al. 1984). Intermediate 16
and 17 (Scheme 2) was obtained following the protocol in
Ref. (Stefanowicz et al. 2016; Dostert et al. 1984) (see
has the form of multiplet. It is formed of 3 overlapping
quartets, calculating the constants of coupling it can be
assume that the C3H proton is axial; 13C NMR (125 MHz,
CDCl3): δ 169.2 (C12); 138.0 (C2’); 137.0 (C1’); 130.1
(C3’); 128.7 (C6’); 126.6 (C4’); 125.4 (C5’); 58.9 (C1, C5);
54.4 (C9); 41.5 (C3); 38.8 (C2, C4); 26.4 (C6, C7); 23.4
(C13); 19.1 (C10); IR (KBr) cm−1: ν3258 (NH), 1650 (CO);
ESI-HRMS m/z calcd for C17H24N2OH (M + H)+
273.1967, found 273.1975.
N-[8-(3-methylbenzyl)-8-azabicyclo[3.2.1]oct-3β-yl]aceta-
mide (10b) Crystallisation from ethyl acetate: hexane 3:1.
Yield: 2.1 g (46.42%) synthesised from 0.016 mol 9; m.p.
135.2–136.2 °C; 1H NMR (500 MHz, CDCl3): δ t 7.20
3
3
(C5’H), J = 7.5; m 7.17 (C2’H, C6’H); d 7.06 (C4’H), J
3
= 7.0; d 5.22 (NH), J = 7.0; m 4.14 (C3H(axial)); s 3.50
(C9H2); pt 3.22 (C1H, C5H); s 2.34 (C10H3); m 2.03 (C2H
(E), C4H(E)); s 1.93 (C13H3); m 1.81 (C6H(E), C7H(E)); m
3
1.72 (C6H(A), C7H(A)); td 1.51 (C2H(A), C4H(A)), JA-A
1
3
Supplementary material). The H NMR spectra of all con-
= 12.5, JA-E = 2.0; 13C NMR (125 MHz, CDCl3): δ 169.2
sidered final compounds are presented in Supplementary
material. The purity of the tested compounds was deter-
mined and was higher than 95% (Fig. 3).
(C12); 139.7 (C1’); 137.8 (C3’); 129.4 (C6’); 128.1 (C5’);
127.6 (C2’); 125.7 (C4’); 58.8 (C1, C5); 56.3 (C9); 41.5
(C3); 38.6 (C2, C4); 26.4 (C6, C7); 23.6 (C13); 21.4 (C10);
IR (KBr) cm−1: ν3265 (NH), 1624 (CO); ESI-HRMS m/z
calcd for C17H24N2OH (M + H)+ 273.1967, found:
273.1966.
General procedure for synthesis of acetamides (10a–f)
The 0.02 mol of 8-azabicyclo[3.2.1]oct-3β-ylacetamide
hydrochloride (9), 0.02 mol of appropriate arylmethyl
chloride (2-methylbenzyl chloride for 10a, 3-methylbenzyl
chloride for 10b or 4-methylbenzyl chloride for 10c, 2-
(chloromethyl)pyridine hydrochloride for 10d, 3-(chlor-
omethyl)pyridine hydrochloride for 10e, 4-(chloromethyl)
pyridine hydrochloride for 10f), 0.09 mol anhydrous K2CO3
and catalytic amount of KI were suspended in 80 mL of
acetone. The reaction mixture was refluxed with stirring for
2–3 h under TLC control. The solution was cooled and
solvent was removed in vacuo, residue was dissolved in
mixture of 40 mL water and 40 mL chloroform (exception is
compound 10e). The solution was extracted with chloro-
form (2 × 40 mL). The combined organic extracts were
dried with magnesium sulphate, filtered, and the solvent
was evaporated in vacuo. The solid residue was purified by
crystallisation.
N-[8-(4-methylbenzyl)-8-azabicyclo[3.2.1]oct-3β-yl]aceta-
mide (10c) Crystallisation from ethyl acetate. Yield: 0.86 g
(63.0%) synthesised from 0.005 mol 9; m.p. 169.1–171.7 °
C; 1H NMR (CDCl3, 500 MHz): δ d 7.24 (C3’H, C5’H), 3J
= 8.5; d 7.12 (C2’H, C6’H), 3J = 7.5; d5.31 (NH), 3J = 7.5;
m 4.13 (C3H(axial)), s 3.48 (C9H2); pt 3.19 (C1H, C5H); s
2.33 (C10H3); m 2.02 (C6H(E), C7H(E); s 1.93 (C12H3); m
1.79 (C2H(E), C4H(E); m 1.70 (C6H(A), C7H(A); td 1.48
(C2H(A), C4H(A), JA–A = 12.5, JA–E = 2.5); 13C NMR
(CDCl3, 125 MHz): δ 169.2 (C11); 136.9 (C1’); 136.3
(C4’); 128.9 (C2’, C6’); 128.5 (C3’, C5’); 58.7 (C1, C5);
56.0 (C9); 41.5 (C3); 38.6 (C2, C4); 26.4 (C6, C70; 23.6
(C12); 21.1 (C10); IR (KBr) cm−1: ν3268 (NH), 1634 (CO);
ESI-HRMS m/z calcd for C17H24N2OH (M + H)+
273.1967, found: 273.1957.
3
3
N-[8-(2-pyridylmethyl)-8-azabicyclo[3.2.1]oct-3β-yl]aceta-
mide (10d) Crystallisation from acetone. Yield: 3.31 g
(74.72%) synthesised from 0.017 mol 9; m.p. 170.2–171.5
N-[8-(2-methylbenzyl)-8-azabicyclo[3.2.1]oct-3β-yl]aceta-
mide (10a) Crystallisation from ethyl acetate: ethanol 4:1.
Yield: 4.5 g (70.2%); m.p. 198.6–199.8 °C; 1H NMR
(500 MHz, CDCl3): δ m 7.31 (C3’H); m 7.14 (C4’H, C5’H,
1
3
°C; H NMR (500 MHz, CDCl3): δ 4d 8.52 (C3’H), J =
5
3
5.0, 4J = 2.0, J = 1.0; td 7.66 (C5’H), J = 8.0, 4J = 1.5; d
C6’H); d 5.53 (NH), J = 7.5; m 4.11 (C3H), 3JA–A = 11.5,
7.53 (C6’H), 3J = 7.5; 4d 7.15 (C4’H), J1 = 7.5, 3J2 = 5.0,
3
3
3JA–E = 7.0*; s 3.45 (C9H2); pt 3.18 (C1H, C5H); s 2.36
(C10H3); m 2.03 (C2H(E), C4H(E)); s 1.92 (C13H3); m
1.79 (C6H(E), C7H(E)); pk 1.71 (C6H(A), C7H(A)); pt
1.47 (C2H(A), C4H(A)) *-the signal of the C3H proton it
4J = 1.5; d 5.34 (NH), 3J = 7.7; m 4.16 (C3H(axial)); s 3.70
(C9H2); pt 3.24 (C1H, C5H); m 2.07 (C2H(E), C4H(E)); s
1.94 (C12H3); m 1.82 (C6H(E), C7H(E)); m 1.74 (C6H(A),
3
3
C7H(A)); td 1.56 (C2H(A), C4H(A)), JA-A = 12.5, JA–E

1910
Medicinal Chemistry Research (2018) 27:1906–1928
Scheme 1 Reagents: a dil. HCl; b NaOH, HCl. q.s.; c NH2OH × HCl; NaHCO3, EtOH; d BuOH/Na, e CHCl3, CH3COCl; f H2, 10%Pd/C, EtOH/
HCl; g ArCl, acetone, K2CO3 anh., KI; h 10%H2SO4; i RCOOH, ClCOOEt, TEA, DMF
N-[8-(3-pyridylmethyl)-8-azabicyclo[3.2.1]oct-3β-yl]aceta-
= 2.5; 13C NMR (125 MHz, CDCl3): δ 169.2 (C11); 160.2
mide (10e) Synthesised from 0.009 mol 9. Reaction was
(C1’); 149.0 (C3’); 136.4 (C5’); 122.5 (C6’); 121.8 (C4’);
carried out under nitrogen atmosphere for 2.5 h. The solu-
59.1 (C1, C5); 58.1 (C9); 41.3 (C3); 38.1 (C2, C4); 26.6
tion was cooled to 0 °C and the 50 mL of 10% H2SO4 was
(C6, C7); 23.5 (C12); IR (KBr) cm−1: ν3250 (NH), 1639
added dropwise with constant stirring. Inorganic precipitate
(CO); ESI-HRMS m/z calcd for C15H21N3ONa (M + Na)+
was filtered and the acetone was evaporated in vacuo. The
282.1582, found: 282.1581.

Medicinal Chemistry Research (2018) 27:1906–1928
H3C H3C
1911
H3C
a
N
N
c
b
N
NH2
O
NOH
COOH
H
15
13
14
16
H3C
X HCl
H
d
N
N
H
N
H
N
H
O
O
H
17
O2N
e
f
N
O2N
H
N
Cl
O
18a-c
H
H2N
N
H
N
O
H
19a-c
Scheme 2 Reagents: a NH2OH x HCl; NaHCO3, EtOH; b Na/PrOH; c ClCOOEt, TEA, DMF, 2-naphthoic acid; d /I/ ClCOOCHClCH3, DMC,
ClCH2CH2Cl, /II/ MeOH; e acetone, K2CO3, anh. KI, o-nitrobenzylchlorides, m-nitrobenzylchlorides, p-nitrobenzylchlorides; f H2, PtO2, EtOH
crude compound 10e (as a solution in 10% H2SO4) was
used in the next step of synthesis without further purifica-
tion because its instability.
R
9
6'
5"
8
4"
4"a
8"a
Z
1'
Z
6"
7"
5'
3"
11
N
7
1
2
X 2'
NH
X
4
2"
Z
3
R3
5
8"
X 3'
R2
4'
1"
N-[8-(4-pyridylmethyl)-8-azabicyclo[3.2.1]oct-3β-yl]aceta-
mide (10f) Crystallisation from acetone. Yield: 3.15 g
(58.4%) synthesised from 0.016 mol 9; m.p. 187.5–190.5 °
6
R1
O
H
R1, R2, R3 = H; X = CH, N; R = H, OCH3; Z = CH, N
R1, R2, R3 = H, NH2; X= CH; R = H, Z = CH
12a-w
19a-c
1
C; H NMR (500 MHz, CDCl3): δ dd 8.53 (C2’H, C6’H),
4
3
3J = 4.5, J = 1.5; d 7.32 (C3’H, C5’H), J = 4.5; d 5.62
(NH), 3J = 7.5; m 4.15 (C3H(axial)); s 3.53 (C9H2); pt 3.17
(C1H, C5H); m 2.02 (C2H(E), C4H(E)); s 1.95 (C12H3); m
1.84 (C6H(E), C7H(E)); pk 1.75 (C6H(A), C7H(A)); td
Fig. 3 Numbering system for NMR spectra interpretation
1.53 (C2H(A), C4H(A)), JA–A = 12.5, JA–E = 2.5; 13C
NMR (125 MHz, CDCl3): δ 169.3 (C11); 149.6 (C2’, C6’);
149.4 (C4’); 123.3 (C3’, C5’); 59.2 (C1, C5); 55.4 (C9);
41.2 (C3); 38.5 (C2, C4); 26.4 (C6, C7); 23.5 (C12); IR
(KBr) cm−1: ν3253 (NH), 1632 (CO); ESI-HRMS m/z calcd
for C15H21N3ONa (M + Na)+ 282.1582, found: 282.1594.
mixture was cooled to room temperature and then alkalised
with saturated aqueous solution of NaOH (to a pH of
10–12), diluted with 80 mL of mixture H2O and CH2Cl2
1:1, next the aqueous phase was extracted with CH2Cl2 (3 ×
40 mL). The combined organic extracts were dried with
magnesium sulphate, filtered, and the solvent was evapo-
rated in vacuo. Due to the high process yield and purity of
the crude products, compound 11a–f were used in sub-
sequent reactions without further purification.
3
3
General procedure for synthesis of amines (11a–f)
A solution of 0.02 mol appropriate acetamide derivative
(10a–f) and 68 mL 10% H2SO4 was refluxed with stirring.
The reaction time was determined using TLC. The reaction
8-(o-tolylmethyl)-8-azabicyclo[3.2.1]oct-3β-ylamine (11a)
Yield: 3.34 g (92.92%) synthesised from 0.02 mol of 10a.

1912
Medicinal Chemistry Research (2018) 27:1906–1928
3
3
8-(m-tolylmethyl)-8-azabicyclo[3.2.1]oct-3β-ylamine
(11b) Yield: 2.2 g (94.60%) synthesised from 0.012 mol of
10b.
3J = 8.5; d 8.07 (NH), J = 8.5; dd 7.86 (C5”H), J = 8.5,
4J = 1.0; m 7.76 (C7”H), J1 = 8.5, J2 = 7.0, J = 1.0; m
3
3
4
3
3
4
7.60 (C6”H), J1 = 8.0, J2 = 7.0, J = 1.0; m 7.39 (C3’H);
m 7.16 (C4’H, C5’H, C6’H); m 4.40 (C3H); s 3.53 (C9H2);
pt 3.29 (C1H, C5H); s 2.41 (C10H3); m 2.11 (C2H(E), C4H
(E)); m 1.96 (C6H(E), C7H(E)); pq 1.83 (C6H(A), C7H
(A)); td 1.76 (C2H(A), C4H(A)), 3JA–A = 12.0, 3JA–E = 2.0;
13C NMR (125 MHz, CDCl3): δ 163.6 (C12); 149.9 (C2”);
146.5 (C8”a); 138.1 (C2’); 137.4 (C4”); 137.1 (C1’); 130.2
(C8”); 130.0 (C7”); 129.7 (C3’); 129.3 (C4”a); 128.9 (C6’);
127.8 (C5”); 127.7 (C6”); 126.7 (C4’); 125.5 (C5’); 118.8
(C3”); 59.2 (C1, C5); 54.5 (C9); 41.8 (C3); 38.9 (C2, C4);
26.6 (C6, C7); 19.3 (C10); IR (KBr) cm−1: ν3304 (NH),
1639 (CO); ESI-HRMS m/z calcd for C25H27N3OH (M +
H)+ 386.2232, found: 386.2224.
8-(p-tolylmethyl)-8-azabicyclo[3.2.1]oct-3β-ylamine (11c)
Yield: 0.63 g (93.0%) synthesised from 0.003 mol of 10c.
Compound 11c was synthesised with minor modification
of general procedure described above.
A solution of 0.003 mol of 10c, 1.1 mL of 10% H2SO4
and 17.2 mL H2O was refluxed with stirring for 4 h. The
reaction mixture was cooled to room temperature, washed
with 20 mL CH2Cl2 to remove dark impurities, then the
aqueous phase was alkalised with a saturated NaOH (to a
pH of 10–12) and extracted with dichloromethane (3 ×
20 mL). The combined organic extracts were dried with
magnesium sulphate, filtered, and the solvent was evapo-
rated in vacuo. The crude compound 11c was used in
subsequent reactions without further purification.
N-[8-(2-methylbenzyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-quino-
line-3-carboxamide (12b) Crystallisation from ethanol.
Yield: 0.50 g (64.93%); m.p. 179.2–180.2 °C; 1H NMR
(500 MHz, CDCl3): δ d 9.23 (C2”H), 4J = 2.0; d 8.52
8-(2-pyridylmethyl)-8-azabicyclo[3.2.1]oct-3β-ylamine
(11d) Yield: 2.28 g (91.02%) synthesised from 0.011 mol
of 10d.
4
3
(C4”H), J = 2.0; d 8.12 (C8”H), J = 8.5; m 7.78 (C7”H),
3J1 = 8.5, 3J2 = 7.0, 4J = 1.5; m 7.58 (C6”H); m 7.34
3
(C3’H); m 7.16 (C4’H, C5’H, C6’H); d 6.23 (NH), J =
8-(3-pyridylmethyl)-8-azabicyclo[3.2.1]oct-3β-ylamine
(11e) Synthesised from crude precipitate of 10e.
8.0; m 4.43 (C3H); s 3.50 (C9H2); pt 3.27 (C1H, C5H); s
2.38 (C10H3); m 2.10 (C2H(E), C4H(E)); m 1.97 (C6H(E),
C7H(E)); pq 1.79 (C6H(A), C7H(A)); td 1.67 (C2H(A),
3
3
8-(4-pyridylmethyl)-8-azabicyclo[3.2.1]oct-3β-ylamine
(11f) Yield: 1.86 g (86.51%) synthesised from 0.012 mol
of 10f.
C4H(A)), JA–A = 12.0, JA–E = 2.0; 13C NMR (125 MHz,
CDCl3): δ 164.9 (C12); 149.2 (C8”a); 148.2 (C2”); 137.9
(C2’); 137.1 (C1’); 135.3 (C4”); 131.1 (C5”); 130.2 (C8”);
129.4 (C3’); 128.8 (C7”); 128.6 (C6’); 127.4 (C4’); 127.3
(C4”a); 126.9 (C3”); 126.7 (C5’); 125.5 (C6”); 59.1 (C1,
C5); 54.5 (C9); 42.5 (C3); 39.0 (C2, C4); 26.6 (C6, C7);
19.2 (C10); IR (KBr) cm−1: ν3308 (NH), 1627 (CO); ESI-
HRMS m/z calcd for C25H27N3ONa (M + Na)+ 408.2052,
found: 408.2051.
General procedure for synthesis of quinoline amides
(12a–w)
A solution of suitable quinolinecarboxylic acid (5 mmol),
ethyl chloroformate (0.5 mL, 5 mmol) and triethylamine
(0.75 mL, 5 mmol) in anhydrous DMF (25 mL) was stirred
for 30 min at 0 °C. A solution of appropriate amine 10a–f
(5 mmol) in anhydrous DMF (15 mL) was added dropwise.
The cooling bath was removed and stirring was continued
for 24 h. The solvent was evaporated in vacuo and to the
residue 10 mL 5% aqueous solution of sodium bicarbonate
was added. Next, the aqueous phase was extracted with
dichloromethane (3 × 20 mL). The combined organic
extracts were dried with magnesium sulphate, filtered, and
the solvent was evaporated in vacuo. Final compounds 12a-
c, 12e-s, and 12v were purified by crystallisation. Com-
pounds 12d, 12t, 12u, and 12w were purified by column
chromatography.
N-[8-(2-methylbenzyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-quino-
line-6-carboxamide (12c) Crystallisation from ethyl acet-
ate:ethanol 1:1. Yield: 0.51 g (66.23%); m.p. 211.4–212.7
1
3
°C; H NMR (500 MHz, CDCl3): δ dd 8.96 (C2”H), J =
4.5, 4J = 2.0; d 8.20 (C8”H), 3J = 8.5; d 8.12 (C4”H), 3J =
3
4
9.0; dd 8.02 (C7”H), J = 9.0, J = 2.0; dd 7.44 (C3”H),
3J1 = 8.5, J2 = 4.0; m 7.35 (C3’H); m 7.16 (C4’H, C5’H,
3
C6’H); d 6.17 (NH), 3J = 8.0; m 4.42 (C3H); s 3.51 (C9H2);
pt 3.27 (C1H, C5H); m 2.10 (C2H(E), C4H(E)); s 2.38
(C10H3); m 1.97 (C6H(E), C7H(E)); pq 1.80 (C6H(A),
3
3
C7H(A)); td 1.66 (C2H(A), C4H(A)), JA–A = 11.5, JA–E
= 2.0; 13C NMR (125 MHz, CDCl3): δ 166.1 (C12); 151.9
(C2”); 149.3 (C8”a); 137.9 (C2’); 137.1 (C1’); 136.9 (C5”);
132.7 (C6”); 130.2 (C4”); 129.9 (C3’); 128.8 (C6’); 127.5
(C4”a); 127.1 (C4’); 127.4 (C7”); 126.8 (C5’); 125.5 (C8”);
121.9 (C3”); 59.1 (C1, C5); 54.5 (C9); 42.4 (C3); 39.0 (C2,
C4); 26.6 (C6, C7); 19.2 (C10); IR (KBr) cm−1: ν3277
N-[8-(2-methylbenzyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-quino-
line-2-carboxamide (12a) Crystallisation from ethanol.
Yield: 0.60 g (77.92%); m.p. 120.8–121.4 °C; 1H NMR
(500 MHz, CDCl3): δ s 8.29 (C3”H, C4”H); d 8.11 (C8”H),

Medicinal Chemistry Research (2018) 27:1906–1928
1913
(NH), 1620 (CO); ESI-HRMS m/z calcd for C25H27N3ONa
(M + Na)+ 408.2052, found: 408.2052.
= 7.5; d 6.24 (NH), 3J = 8.0; m 4.44 (C3H); s 3.52 (C9H2);
pt 3.28 (C1H, C5H); s 2.34 (C10H3); m 2.09 (C2H(E), C4H
(E)); m 1.97 (C6H(E), C7H(E)); pq 1.78 (C6H(A), C7H
(A)); td 1.70 (C2H(A), C4H(A)), 3JA–A = 12.5, 3JA–E = 2.5;
13C NMR (125 MHz, CDCl3): δ 164.9 (C12); 149.2 (C8”a);
148.2 (C2”); 139.8 (C1’); 137.8 (C3’); 135.3 (C4”); 131.1
(C5”); 129.4 (C8”); 129.3 (C6’); 128.7 (C7”); 128.1 (C5’);
127.6 (C2’); 127.5 (C4’); 127.3 (C3”); 126.9 (C4”a); 125.6
(C6”); 58.8 (C1, C5); 56.3 (C9); 42.4 (C3); 38.6 (C2, C4);
26.5 (C6, C7); 21.4 (C10); IR (KBr) cm−1: ν3387 (NH),
1632 (CO); ESI-HRMS m/z calcd for C25H27N3OH (M +
H)+ 386.2232, found: 386.2238.
N-[8-(2-methylbenzyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-4-
methoxyquinoline-2-carboxamide (12d) Column chroma-
tography chloroform: methanol (9: 1 v/v).Yield: 0.68 g
(81.91%); m.p. 54.5–55.9 °C; 1H NMR (500 MHz, CDCl3):
3
4
3
δ dd 8.21 (C8”H), J = 8.5, J = 1.0; d 8.02 (C5”H), J =
3
3
4
8.5; m 7.72 (C6”H), J1 = 8.0, J2 = 6.5, J = 1.5; s 7.69
3
3
4
(C3”H); m 7.54 (C7”H), J = 8.5, J2 = 7.0, J = 1.5; m
7.39 (C3’H); m 7.16 (C4’H, C5’H, C6’H); d 6.11 (NH), 3J
= 8.5; m 4.38 (C3H); s 4.11 (OC13H3); s 3.53 (C9H2); pt
3.29 (C1H, C5H); s 2.41 (C10H3); m 2.12 (C2H(E), C4H
(E)); m 1.95 (C6H(E), C7H(E)); pq 1.83 (C6H(A), C7H
(A)); pt 1.76 (C2H(A), C4H(A)); 13C NMR (125 MHz,
CDCl3): δ 163.9 (C12); 163.6 (C4”); 151.4 (C2”); 147.5
(C8”a); 138.1 (C2’); 137.1 (C1’); 130.2 (C7”); 130.2 (C3’);
129.1 (C8”); 128.9 (C6’); 126.7 (C6”); 126.7 (C4’); 125.5
(C5’); 122.0 (C4”a); 121.9 (C5”); 97.8 (C3”); 59.3 (C1,
C5); 56.1 (C13); 54.4 (C9); 41.8 (C3); 38.7 (C2, C4); 26.6
(C6, C7); 19.3 (C10); IR (KBr) cm−1: ν 3380 (NH), 1674
(CO); ESI-HRMS m/z calcd for C26H29N3O2H (M + H)+
416.2338, found: 416.2325.
N-[8-(3-methylbenzyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-quino-
line-6-carboxamide (12g) Crystallisation from 2-propanol.
1
Yield: 0.47 g (61.03 %); m.p. 174.4–175.5 °C; H NMR
3
4
(500 MHz, CDCl3): δ dd 8.97 (C2”H), J = 4.0, J = 2.0; d
8.25 (C5”H), 4J = 2.0; dd 8.20 (C8”H), 3J = 8.0, 5J = 1.0; d
8.13 (C4”H), J = 8.5; dd 8.01 (C7”H), J = 8.5, J = 2.0;
dd 7.45 (C3”H), J1 = 8.0, J2 = 4.0; t 7.21 (C5’H), J =
3
3
4
3
3
3
3
7.5; m 7.18 (C2’H, C6’H); d 7.07 (C4’H), J = 7.0; d 6.19
(NH), 3J = 8.0; m 4.43 (C3H); s 3.53 (C9H2); pt 3.29 (C1H,
C5H); s 2.35 (C10H3); m 2.09 (C2H(E), C4H(E)); m 1.97
(C6H(E), C7H(E)); pq 1.80 (C6H(A), C7H(A)); td 1.70
3
3
N-[8-(3-methylbenzyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-quino-
line-2-carboxamide (12e) Crystallisation from 2-propanol.
Yield: 0.41 g (53.24%); m.p. 113.8–114.7 °C; 1H NMR
(500 MHz, CDCl3): δ d 8.29 (C4”H), 3J = 8.5; d 8.27
(C2H(A), C4H(A)), JA–A = 12.0, JA–E = 2.0; 13C NMR
(125 MHz, CDCl3): δ 166.0 (C12); 151.9 (C2”); 149.3
(C8”a); 139.8 (C1’); 137.8 (C3’); 136.9 (C5”); 132.7 (C6”);
130.0 (C4”); 129.3 (C6’); 128.1 (C5’); 127.6 (C2’); 127.6
(C4”a); 127.4 (C4’); 127.0 (C7”); 125.6 (C8”); 121.9 (C3”);
58.8 (C1, C5); 56.3 (C9); 42.3 (C3); 38.6 (C2, C4); 26.5
(C6, C7); 21.4 (C10); IR (KBr) cm−1: ν3362 (NH), 1632
(CO); ESI-HRMS m/z calcd for C25H27N3ONa (M + Na)+
408.2052, found: 408.2054.
3
3
3
(C3”H), J = 8.5; d 8.12 (NH), J = 8.5; d 8.09 (C8”H), J
3
3
4
= 8.5; m 7.75 (C7”H), J1 = 9.0, J2 = 7.0, J = 1.0; dd
3
4
3
7.85 (C5”H), J = 8.0, J = 0.5; m 7.60 (C6”H), J1 = 8.0,
3J2 = 7.0, J = 1.0; m 7.22 (C2’H, C5’H, C6’H); m 7.07
4
(C4’H); m 4.41 (C3H); s 3.55 (C9H2); pt 3.30 (C1H, C5H);
s 2.36 (C10H3); m 2.10 (C2H(E), C4H(E)); m 1.95 (C6H
(E), C7H(E)); pq 1.82 (C6H(A), C7H(A)); td 1.78 (C2H(A),
N-[8-(3-methylbenzyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-4-
3
3
C4H(A)), JA–A = 12.5, JA–E = 2.0; 13C NMR (125 MHz,
CDCl3): δ 163.6 (C12); 149.9 (C2”); 146.4 (C8”a); 139.9
(C1’); 137.8 (C3’); 137.4 (C4”); 130.0 (C8”); 129.7 (C7”);
129.4 (C6’); 129.2 (C4”a); 128.1 (C5’); 127.8 (C5”); 127.7
(C6”); 127.5 (C2’); 125.7 (C4’); 118.8 (C3”); 58.8 (C1,
C5); 56.4 (C9); 41.6 (C3); 38.5 (C2, C4); 26.5 (C6, C7);
21.5 (C10); IR (KBr) cm−1: ν3285 (NH), 1647 (CO); ESI-
HRMS m/z calcd for C25H27N3OH (M + H)+ 386.2232,
found: 386.2241.
methoxyquinoline-2-carboxamide
(12h) Crystallisation
from ethyl acetate. Yield: 0.35 g (42.16%); m.p.
1
116.1–118.3 °C; H NMR (500 MHz, CDCl3): δ dd 8.21
3
4
3
(C8”H), J = 8.5, J = 1.0; d 8.16 (NH), J = 8.5; d 8.01
3
3
3
4
(C5”H), J = 8.5; m 7.72 (C6”H), J1 = 8.5, J2 = 7.0, J =
1.5; s 7.69 (C3”H); m 7.54 (C7”H), 3J1 = 8.0, 3J2 = 6.5, 4J =
1.0; m 7.21 (C2’H, C5’H, C6’H); d 7.07 (C4’H), 3J = 6.5; m
4.39 (C3H); s 4.11 (OC13H3); s 3.55 (C9H2); pt 3.30 (C1H,
C5H); s 2.36 (C10H3); m 2.10 (C2H(E), C4H(E)); m 1.94
(C6H(E), C7H(E)); pq 1.82 (C6H(A), C7H(A)); pt 1.79 (C2H
(A), C4H(A)); 13C NMR (125 MHz, CDCl3): δ 163.8 (C12);
163.6 (C4”); 151.4 (C2”); 147.5 (C8”a); 139.9 (C1’); 137.8
(C3’); 130.2 (C7”); 129.4 (C6’); 129.1 (C8”); 128.1 (C5’);
127.6 (C2’); 126.7 (C6”); 125.7 (C4’); 122.0 (C4”a); 121.9
(C5”); 97.8 (C3”); 58.8 (C1, C5); 56.3 (C13); 56.1 (C9); 41.7
(C3); 38.4 (C2, C4); 26.6 (C6, C7); 21.4 (C10); IR (KBr)
cm−1: ν3285 (NH), 1651 (CO); ESI-HRMS m/z calcd for
C26H29N3O2H (M + H)+ 416.2338, found: 416.2329.
N-[8-(3-methylbenzyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-quino-
line-3-carboxamide (12f) Crystallisation from ethanol.
Yield: 0.40 g (51.94%); m.p. 194.0–194.7 °C; 1H NMR
(500 MHz, CDCl3): δ d 9.23 (C2”H), 4J = 2.5; d 8.52
(C4”H), 4J = 2.0; d 8.13 (C8”H), 3J = 8.5; dd 7.86 (C5”H),
4
3
3
4
3J = 8.0, J = 1.0; m 7.78 (C7”H), J1 = 8.0, J2 = 6.5, J
= 1.5; m 7.59 (C6”H), 3J1 = 8.0, 3J2 = 7.0, 4J = 1.0; m 7.20
(C5’H), 3J = 7.5; m 7.19 (C2’H, C6’H); m 7.06 (C4’H), 3J

1914
Medicinal Chemistry Research (2018) 27:1906–1928
N-[8-(4-methylbenzyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-quino-
line-2-carboxamide oxalate (12i) Crystallisation from
ethanol/diethyl ether 2:1. Yield: 0.53 g (57.6%); m.p.
m 1.96 (C2H(E), C4H(E)); pq 1.78 (C6H(A), C7H(A)); td
1.67 (C2H(A), C4H(A), JA-A = 12.0, JA-E = 2.5; 13C
NMR (125 MHz, CDCl3): δ 166.0 (C11); 151.9 (C2”);
149.3 (C8”a); 136.9 (C5”); 136.9 (C1’); 136.4 (C4’); 132.7
(C6”); 130.0 (C4”); 128.9 (C2’, C6’); 128.5 (C3’, C5’);
127.6 C4”a); 127.4 (C8”); 127.1 (C7”); 121.9 (C3”); 58.7
(C1, C5); 56.1 (C9); 42.4 (C3); 38.7 (C2, C4); 26.5 (C6,
C7); 21,1 (C10); IR (KBr) cm−1: ν3345 (NH), 1635 (CO);
ESI-HRMS m/z calcd for C25H28N3O (M + H)+ 386.2232,
found: 386.2240.
3
3
1
215.0–215.4 °C; H NMR (500 MHz, (CD3)2SO): δ d 8.78
3
(NH); d 8.56 (C4’H), J = 8.5; m 8.15 (C3”H, C8”H); d
8.08 (C5”H), 3J = 8.0; t 7.87 (C7”H), 3J = 8.0; t 7.72
(C6”H), 3J = 8.0; d 7.51 (C3’H, C5’H), 3J = 7.5; d7.25
(C2’H, C6’H), 3J = 7.5; m 4.42 (C3H(axial)); s 4.26 (C9H2;
bs 3.76 (C1H, C5H); s 2.32 (C10H3); m 2.20–2.34 C2H(E),
C4H(E), C6H(E), C7H(E); m 1.90–2.03 (C2H(A), C4H(A),
C6H(A), C7H(A); 13C NMR (125 MHz, (CD3)2SO): δ
164.6 (C11); 163.6 (C8”a); 149.9 (C2”); 145.9 (C4”); 138.5
(C1’); 137.5 (C4’); 130.5 (C4”a); 130.4 (C2’, C6’); 129.4
(C3’, C5’); 129.2 (C8’); 128.8 (C7”); 128.2 (C5”); 128.1
(C6”); 59.4 (C1, C5); 51.7 (C9); 39.5 (C3); 33.3 (C2, C4);
24.7 (C6, C7); 20.8 (C10); IR (KBr) cm−1: ν3385 (NH),
1688 (CO); ESI-HRMS m/z calcd for C25H27N3OH (M +
H)+ 386.2232, found: 386.2216. Based on the analysis of
1H and 13C NMR spectra, it was found that the resulting
compound was monooxolate salt protonated at the 8-
position of the tropane.
N-[8-(2-pyridylmethyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-quino-
line-2-carboxamide (12l) Crystallisation from ethyl acet-
ate. Yield: 0.26 g (43.34%); m.p. 150.2–151.0 °C; 1H NMR
(500 MHz, CDCl3): δ 4d 8.55 (C3’H), 3J = 5.0, 4J = 2.0, 5J
= 1.0,; s 8.29 (C4”H, C3”H); d 8.14 (NH), 3J = 9.0; d 8.10
(C8”H), 3J = 8.5; 4d 7.86 (C5”H), 3J = 8.0; m 7.77 (C7”H),
3
4
3
4
3J1 = 8.5, J2 = 7.0, J = 1.5; td 7.68 (C5’H), J = 7.5, J
= 2.0; m 7.61 (C6”H, C6’H); 4d 7.16 (C4’H) 3J1 = 7.5, 3J2
= 4.5, 4J = 1.0; m 4.44 (C3H(axial)); s 3.79 (C9H2); pt 3.34
(C1H, C5H); m 2.14 (C2H(E), C4H(E)); m 1.96 (C6H(E),
C7H(E)); m 1.86 (C6H(A), C7H(A), C2H(A), C4H(A));
13C NMR (125 MHz, CDCl3): δ 163.6 (C11); 160.3 (C1’);
149.9 (C2”); 149.0 (C3’); 143.4 (C8”a); 137.4 (C4”); 136.4
(C5’); 130.0 (C8”); 129.7 (C7”); 129.2 (C4”a); 127.8 (C5”);
127.7 (C6”); 122.6 (C6’); 121.8 (C4’); 118.8 (C3”); 59.2
(C1, C5); 58.1 (C9); 41.4 (C3); 37.9 (C2, C4); 26.7 (C6,
C7); IR (KBr) cm−1: ν3394 (NH), 1679 (CO); ESI-HRMS
m/z calcd for C23H24N4ONa (M + Na)+ 395.1848, found:
395.1858.
N-[8-(4-methylbenzyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-quino-
line-3-carboxamide (12j) Crystallisation from ethyl acet-
ate:ethanol 7:1. Yield: 0.50 g (68.0%); m.p. 219.5–220.8 °
C; 1H NMR (500 MHz, CDCl3): δ d 9.23 (C2”H), 4J = 2.0;
4
3
d 8.52 (C4”H), J = 2.0; d 8.13 (C8”H), J = 8.5; d 7.86
(C5”H), 3J = 8.0; m 7.78 (C7”H), 3J1 = 8.5, 3J2 = 6.5, 4J =
3
1.0; m 7.59 (C6”H); d 7.26 (C3’H, C5’H), J = 8.0;d 7.12
(C2’H, C6’H), 3J = 8.0; d 6.21 (NH), 3J = 8.0; m 4.44
(C3H(axial)), s 3.52 (C9H2), bs 3.27 (C1H, C5H); s 2.34
(C10H3); m 2.08 (C6H(E), C7H(E); m 1.96 (C2H(E), C4H
(E); pq 1.78 (C6H(A), C7H(A); td 1.69 C2H(A), C4H(A),
N-[8-(2-pyridylmethyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-quino-
line-3-carboxamide (12m) Crystallisation from acetone.
Yield: 0.27 g (43.04%); m.p. 169.4–170.5 °C; 1H NMR
(500 MHz, CDCl3): δ d 9.24 (C2”H), 4J = 2.0;m 8.53
3JA–A = 12.0, JA–E = 2.0; 13C NMR (125 MHz, CDCl3): δ
3
164.9 (C11); 149.2 (C8”a); 148.2 (C2’); 136.8 (C1’); 136.4
(C4’); 135.3 (C4”); 131.1 (C5”); 129.4 (C8”); 128.9 (C2’,
C6’); 128.7 (C7’); 128.5 (C3’, C5’); 127.5 (C6”); 127.3
(C3”); 126.9 (C4”a); 58.7 (C1, C5); 56.1 (C9); 42.4
(C3); 38.6 (C2, C4); 26.5 (C6, C7); 21.1 (C10); IR
(KBr) cm−1: ν3315 (NH), 1632 (CO); ESI-HRMS m/z
calcd for C25H27N3OH (M + H)+ 386.2232, found:
386.2241.
3
(C3’H, C4”H); 4d 8.13 (C8”H), J = 8.5; 4d 7.87 (C5”H),
4
5
3
3
3J = 8.0, J = 1.0, J = 0.5; m 7.78 (C7”H), J1 = 8.5, J2
4
3
4
= 6.5, J = 1.5; td 7.66 (C5’H), J = 8.0, J = 2.0; m 7.60
(C6”H), 3J1 = 8.0, 3J2 = 7.0, 4J = 1.0; dt 7.55 (C6’H), 3J =
6.5, J = 5J = 1.0; 4d 7.16 (C4’H), J1 = 7.0, J2 = 5.0, J
4
3
3
4
3
= 1.5; d .31 (NH), J = 8.0; m 4.46 (C3H(axial)); s 3.74
(C9H2); pt 3.31 (C1H, C5H); m 2.13 (C2H(E), C4H(E)); m
1.98 (C6H(E), C7H(E)); pk 1.84 (C6H(A), C7H(A)); td
2,3
3
N-[8-(4-methylbenzyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-quino-
line-6-carboxamide (12k) Crystallisation from ethyl acet-
ate:ethanol 1:1. Yield: 0.46 g (59.74%); m.p. 211.9–213.0 °
C; 1H NMR (500 MHz, CDCl3): δ dd 8.97 (C2:H), 3J = 4.0,
4J = 2.0; d 8.25 (C5”H), 4J = 2.0; dd 8.20 (C8”H), 3J = 8.0,
1.77 (C2H(A), C4H(A)),
J
= 11.5, JA–E = 2.0; 13C
A–A
NMR (125 MHz, CDCl3): δ 164.9 (C11); 160.1 (C1’);
149.2 (C8”a); 149.0 (C3’); 148.2 (C2”); 136.4 (C5’); 135.3
(C4”); 131.1 (C5”); 129.3 (C8”); 128.7 (C7”); 127.4 (C6”);
127.2 (C3”); 126.9 (C4”a); 122.6 (C6’); 121.9 (C4’); 59.1
(C1, C5); 58.1 (C9); 42.2 (C3); 38.0 (C2, C4); 26.7 (C6,
C7); IR (KBr) cm−1: ν3283 (NH), 1631 (CO); ESI-HRMS
m/z calcd for C23H24N4ONa (M + Na)+ 395.1848, found:
395.1857.
3
5J = 1.0; d 8.13 (C4”), J = 8.5; dd 8.01 (C7”H),3J = 9.0,
4J = 2.0; dd 7.44 (C3”H) 3J1 = 8.5, 3J2 = 4.0; d 7.27 (C3’H,
3
4
C5’H), J = 7.5; d 7.12 (C2’H, C6’H), J = 8.0; d 6.18
(NH), 3J = 8.0; m 4.43 (C3H(axial)), s 3.52 (C9H2); bs 3.27
(C1H, C5H); s 2.34 (C10H3); m 2.08 (C6H(E)), C7H(E));

Medicinal Chemistry Research (2018) 27:1906–1928
1915
N-[8-(2-pyridylmethyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-quino-
line-6-carboxamide (12n) Crystallisation from acetone.
Yield: 0.50 g (83.35%); m.p. 193.7–194.5 °C; 1H NMR
C5H); m 2.10 (C2H(E), C4H(E)); m 1.96 (C6H(E), C7H
(E)); pk 1.84 (C6H(A), C7H(A)); td 1.78 (C2H(A), C4H
(A)), JA–A = 12.5, JA–E = 2.0; 13C NMR (125 MHz,
CDCl3): δ 163.6 (C11); 150.0 (C2’); 149.8 (C2”); 148.4
(C4’); 146.4 (C8”a); 137.4 (C4”); 135.4 (C1’); 135.4 (C6’);
130.0 (C8”); 129.6 (C7”); 129.2 (C4”a); 127.8 (C5”); 127.7
(C6”); 123.3 (C5’); 118.8 (C3”); 58.9 (C1, C5); 53.7 (C9);
3
3
3
4
(500 MHz, CDCl3): δ dd 8.97 (C2”H), J = 4.0, J = 1.5;
dd 8.54 (C3’H), 3J = 4.5, 4J = 1.0; d 8.25 (C5”H), 4J = 1.5;
dd 8.20 (C8”H), 3J = 8.5, 5J = 0.5; d 8.13 (C4”H), 3J = 9.0;
3
4
3
dd 8.02 (C7”H), J = 9.0, J = 2.0; dd 7.45 (C3”H), J1 =
3
3
4
8.5, J2 = 4.0; td 7.66 (C5’H), J = 7.5, J = 2.0; d 7.55
41.4 (C3); 38.3 (C2, C4); 26.5 (C6, C7); IR (KBr) cm−1
:
(C6’H), 3J = 7.5; td 7.16 (C4’H), 3J = 6.5; d 6.24 (NH), J
ν3369 (NH), 1678 (CO); ESI-HRMS m/z calcd for
3
= 8.5; m 4.45 (C3H(axial)); s 3.75 (C9H2); pt 3.31 (C1H,
C5H); m 2.13 (C2H(E), C4H(E)); m 1.98 (C6H(E), C7H
(E)); pk 1.82 (C6H(A), C7H(A)); td 1.76 (C2H(A), C4H
C23H24N4ONa (M + Na)+ 395.1848, found: 395.1838.
N-[8-(3-pyridylmethyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-quino-
line-3-carboxamide (12q) Crystallisation from ethyl acet-
2,3
3
(A)),
J
= 12.0, JA–E = 2.0; 13C NMR (125 MHz,
A–A
1
CDCl3): δ 166.0 (C11); 160.1 (C1’); 151.9 (C2”); 149.3
(C8”a); 149.0 (C3’); 136.9 (C5”); 136.7 (C6”); 136.4 (C5’);
129.9 (C4”); 127.5 (C4”a); 127.4 (C7”); 127.0 (C8”); 122.5
(C6’); 121.9 (C3”); 121.9 (C4’); 59.1 (C1, C5); 58.1 (C9);
ate. Yield: 0.52 g (69%); m.p. 138.3–146.2 °C; H NMR
(500 MHz, CDCl3): δ d 9.25 (C2”H), 4J = 2.0; d 8.59
4
4
(C2’H), J = 1.5; d 8.56 (C4”H), J = 2.0; dd 8.50 (C4’H),
3J = 5.0, J = 2.0; dd 8.13 (C8”H), J = 8.5, J = 1.0; dd
4
3
4
42.1 (C3); 38.0 (C2, C4); 26.7 (C6, C7); IR (KBr) cm−1
:
7.88 (C5”H), J = 8.0, J = 1.5; m 7.79 (C7”H), J1 = 8.5,
3
4
3
4
3
4
ν3268 (NH), 1635 (CO); ESI-HRMS m/z calcd for
3J2 = 7.0, J = 1.5; dt 7.74 (C6’H), J = 8.0, J = 2.0; m
7.60 (C6”H), 3J1 = 8.5, 3J2 = 7.0, 4J = 1.5; 4d 7.26 (C5’H),
3J1 = 8.0, 3J2 = 5.0, 5J = 0.5; d 6.45 (NH), 3J = 8.5; m 4.45
(C3H(axial)); s 3.57 (C9H2); pt 3.26 (C1H, C5H); m 2.11
C23H24N4ONa (M + Na)+ 395.1848, found 395.1848.
N-[8-(2-pyridylmethyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-4-
methoxyquinoline-2-carboxamide
(12o) Crystallisation
(C2H(E), C4H(E)); m 1.98 (C6H(E), C7H(E)); pk 1.83
3
from diisopropyl ether. Yield: 0.57 g (75.06%); m.p.
(C6H(A), C7H(A)); td 1.71 (C2H(A), C4H(A)), JA–A
=
1
3
132.5–133.0 °C; H NMR (500 MHz, CDCl3): δ 4d 8.54
11.0, JA–E = 2.5; 13C NMR (125 MHz, CDCl3): δ 165.0
(C11); 150.0 (C2’); 149.2 (C8”a); 148.4 (C4’); 148.2 (C2”);
136.3 (C6’); 135.4 (C4”); 135.3 (C1’); 131.2 (C5”); 129.3
(C8”); 128.7 (C7”); 127.5 (C6”); 127.2 (C3”); 126.9
(C4”a); 123.4 (C5’); 59.0 (C1, C5); 53.8 (C9); 42.2 (C3);
38.5 (C2, C4); 26.4 (C6, C7); IR (KBr) cm−1: ν3250 (NH),
1653 (CO); ESI-HRMS m/z calcd for C23H24N4ONa (M +
Na)+ 395.1848, found: 395.1844.
3
4
5
3
(C3’H), J = 4.5, J = 1.5, J = 0.5; 4d 8.21 (C8”H), J =
8.5, 4J = 1.5, 5J = 1.0; d 8.18 (NH), 3J = 9.0; 4d 8.02
3
4
5
3
(C5”H), J = 8.5, J = 1.5, J = 1.0; m 7.73 (C6”H), J1 =
8.5, 3J2 = 7.0, 4J = 1.5; s 7.69 (C3”H); m 7.55 (C7”H), 3J1
3
4
3
4
= 8.5, J2 = 7.0, J = 1.5; td 7.68 (C5’H), J = 7.5, J =
1.5; d 7.60 (C6’H), 3J = 7.5; 4d 7.16 (C4’H), 3J1 = 7.5, 3J2
= 5.0, 4J = 1.5; m 4.41 (C3H(axial)); s 4.12 (OCH3); s 3.78
(C9H2); pt 3.33 (C1H, C5H); m 2.14 (C2H(E), C4H(E)); pk
1.82 (C6H(A), C7H(A), C2H(A), C4H(A)); m 1.46 (C6H
(E), C7H(E)); 13C NMR (125 MHz, CDCl3): δ 163.8 (C11);
163.5 (C4”); 160.3 (C1’); 151.4 (C2”); 149.0 (C3’); 147.5
(C8”a); 136.4 (C5’); 130.2 (C7”); 129.1 (C8”); 126.7 (C6”);
122.6 (C6’); 122.0 (C4”a); 121.9 (C5”); 121.8 (C4’); 97.8
(C3”); 59.2 (C1, C5); 58.2 (C9); 56.1 (OCH3); 41.5 (C3);
37.9 (C2, C4); 26.8 (C6, C7); IR (KBr) cm−1: ν3372 (NH),
1671 (CO); ESI-HRMS m/z calcd for C24H26N4O2Na (M +
Na)+ 425.1953, found: 425.1948.
N-[8-(3-pyridylmethyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-quino-
line-6-carboxamide (12r) Crystallisation from ethyl acetate.
Yield: 0.43 g (57%); m.p. 158.3–162.5 °C; 1H NMR
3
4
(500 MHz, CDCl3): δ dd 8.93 (C2”H), J = 4.0, J = 2.0; dd
4
4
3
8.58 (C2’H), J1 = 2.0, J2 = 1.0; dd 8.49 (C4’H), J = 4.5,
4J = 2.0; d 8.29 (C5”H), J = 2.0; 4d 8.18 (C8”H), J = 8.5,
4
3
5J = 1.0, J = 0.5; d 8.11 (C4”H), J = 8.5; dd 8.06 (C7”H),
p
3
3J = 8.5, 4J = 2.0; dt 7.71 (C6’H), 3J = 8.0, 4J = 2.0; dd 7.43
3
3
3
3
(C3”H), J1 = 8.5, J2 = 4.0; 4d 7.25 (C5’H), J1 = 8.0, J2
= 4.5, 5J = 1.0; d 6.73 (NH), 3J = 8.5; m 4.43 (C3H(axial)); s
3.55 (C9H2); pt 3.24 (C1H, C5H); m 2.08 (C2H(E), C4H(E));
m 1.95 (C6H(E), C7H(E)); pk 1.81 (C6H(A), C7H(A)); td
N-[8-(3-pyridylmethyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-quino-
line-2-carboxamide (12p) Crystallisation from ethyl acet-
1
3
3
ate. Yield: 0.52 g (69%); m.p. 143.0–143.4 °C; H NMR
1.70 (C2H(A), C4H(A)), JA–A = 12.5, JA–E = 2.0; 13C
NMR (125 MHz, CDCl3): δ 166.2 (C11); 151.8 (C2”); 149.9
(C2’); 149.1 (C8”a); 148.2 (C4’); 136.9 (C5”); 136.3 (C6’);
135.3 (C1’); 132.7 (C6”); 129.7 (C4”); 127.5 (C7”); 127.5
(C4”a); 127.2 (C8”); 123.3 (C5’); 121.8 (C3”); 58.9 (C1, C5);
53.8 (C9); 42.1 (C3); 38.3 (C2, C4); 26.4 (C6, C7); IR (KBr)
cm−1: ν3233 (NH), 1628 (CO); ESI-HRMS m/z calcd for
C23H24N4ONa (M + Na)+ 395.1848, found 395.1839.
(500 MHz, CDCl3): δ d 8.61 (C2’H), 4J = 1.5; dd 8.51
3
4
(C4’H), J = 4.5, J = 1.5; s 8.29 (C3”H, C4”H); bs 8.13
3
3
(NH); d 8.10 (C8”H), J = 8.5; 4d 7.86 (C5”H), J = 8.5,
4J = 1.5, 5J = 0.5; dt 7.78 (C6’H), 3J = 7.5; m 7.76 (C7”H),
3J1 = 8.5, 3J2 = 7.0, 4J = 1.5; m 7.61 (C6”H), 3J1 = 8.0, 3J2
4
3
3
5
= 6.5, J = 1.0; 4d 7.27 (C5’H), J1 = 8.0, J2 = 4.5, J =
0.5; m 4.41 (C3H(axal)); s 3.59 (C9H2); pt 3.28 (C1H,

1916
Medicinal Chemistry Research (2018) 27:1906–1928
N-[8-(3-pyridylmethyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-4-
C7H(A)); td 1.75 (C2H(A), C4H(A), 3JA–A = 12.5, 3JA–E
=
methoxyquinoline-2-carboxamide
(12s) Crystallisation
2.5, C3H equatorial conformation: d 9.21 (C2”H), 4J = 2.0;
m* 8.54 (C4”H); m* 8.54 (C2’H, C6’H); m* 8.14 (C8”H);
d 7.90 (C5”H), 3J = 7.5; m* 7.80 (C7”H); m* 7.60 (C6”H);
from acetone. Yield: 0.55 g (68%); m.p. 162.6–165.5 °C;
1H NMR (500 MHz, CDCl3): δ d 8.61 (C2’H), 4J = 1.5; dd
3
4
3
3
8.51 (C4’H), J = 4.5, J = 1.5; dd 8.21 (C8”H), J = 8.5,
m* 7.34 (C3’H, C5’H); d 6.75 (NH), J = 6.5; pq 4.40
4J = 1.0; d 8.16 (NH), J = 8.5; 4d 8.02 (C5”H), J = 8.0,
(C3H); s* 3.57 (C9H2); m* 3.25 (C1H, C5H); m 2.35 (C6H
(E), C7H(E)); m 2.23 (C2H(E), C4H(E)); pq 1.94 (C6H(A),
C7H(A)); m* 1.84 (C2H(A), C4H(A)); 13C NMR
(125 MHz, CDCl3): δ C3H axial conformation: 165.1
(C11); 149.6 (C2’, C6’); 149.3 (C4’); 149.1 (C8”a); 148.3
(C2”); 135.4 (C4”); 131.1 (C5”); 129.3 (C8”); 128.7 (C7”);
127.5 (C6”); 127.3 (C3”); 126.9 (C4”a); 123.4 (C3’, C5’);
59.4 (C1, C5); 55.5 (C9); 42.1 (C3); 38.5 (C2, C4); 26.5
(C6, C7), C3H equatorial conformation: 164.7 (C11);
149.7 (C2’, C6’); 149.2 (C4’); 149.2 (C8”a); 147.7 (C2”);
135.5 (C4”); 131.2 (C5”); 129.3 (C8”); 128.7 (C7”); 127.6
(C6”); 127.4 (C3”); 126.9 (C4”a); 123.3 (C3’, C5’); 58.4
(C1, C5); 55.7 (C9); 42.6 (C3); 36.7 (C2, C4); 26.5 (C6,
C7), *-there is a increase in the number of signals in the 1H
NMR spectra, suggesting the presence of a mixture of
compounds. distinct multiplets of the C3H proton (in the
proton spectrum) allows the conclusion that there is a
mixture of two isomers: one (β) with an axial multiplet of
the C3H proton (12 lines) and one (α) with an equatorial
multiplet of the C3H proton (4 lines). The molar ratio of the
β form to the α form is 2:1; IR (KBr) cm−1: ν3292 (NH),
1636 (CO); ESI-HRMS m/z calcd for C23H24N4ONa (M +
Na)+ 395.1848, found: 395.1844.
3
3
4J = 5J = 1.0; dt 7.78 (C6’H), J = 7.5, J = 2.0; m 7.73
3
4
3
3
4
(C6”H), J1 = 8.5, J2 = 6.5, J = 1.5; s 7.69 (C3”H); m
7.55 (C7”H), 3J1 = 8.5, 3J2 = 7.0, 4J = 1.5; 4d 7.27 (C5’H),
3J1 = 7.5, J2 = 4.5, J = 0.5; m 4.39 (C3H(axial)); s 4.11
(OCH3); s 3.60 (C9H2); pt 3.27 (C1H, C5H); m 2.10 (C2H
(E), C4H(E)); m 1.95 (C6H(E), C7H(E)); pk 1.84 (C6H(A),
3
5
3
3
C7H(A)); td 1.78 (C2H(A), C4H(A)), JA–A = 12.0, JA–E
= 2.0; 13C NMR (125 MHz, CDCl3): δ 163.9 (C11); 163.5
(C4”); 151.3 (C2”); 150.0 (C2’); 148.4 (C4’); 147.5 (C8”a);
136.2 (C6’); 135.4 (C1’); 130.2 (C7”); 129.1 (C8”); 126.7
(C6”); 123.3 (C5’); 122.0 (C4”a); 121.9 (C5”); 97.7 (C3”);
58.9 (C1, C5); 56.1 (OCH3), 53.7 (C9); 41.5 (C3); 38.2 (C2,
C4); 26.5 (C6, C7); IR (KBr) cm−1: ν3326 (NH), 1663
(CO); ESI-HRMS m/z calcd for C24H26N4O2Na (M + Na)+
425.1953, found: 425.1934.
N-[8-(4-pyridylmethyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-quino-
line-2-carboxamide
(12t) Column
chromatography
chloroform: methanol (98: 2 v/v). Yield: 0.46 g (61.74%);
1
m.p. 143.0–145.7 °C; H NMR (500 MHz, CDCl3): δ dd
8.56 (C2’H, C6’H), 3J = 5.5, 4J = 1.5; s 8.30 (C3”H,
3
4
C4”H); pd 8.11 (C8”H, NH); dd 7.87 (C5”H), J = 8.0, J
= 0.5; m 7.77 (C7”H), 3J1 = 8.5, 3J2 = 7.0, 4J = 1.5; m 7.61
(C6”H); d 7.37 (C3’H, C5’H), 3J = 5.5; m 4.42 (C3H
N-[8-(4-pyridylmethyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-quino-
line-6-carboxamide (12v) Crystallisation from acetone.
Yield: 0.31 g (41.61%); m.p. 182.0–183.3 °C; 1H NMR
3
3
(axial)), JA–A = 13.0, JA–E = 9.0; s 3.60 (C9H2); pt 3.27
(C1H, C5H); m 2.09 (C2H(E), C4H(E)); m 1.98 (C6H(E),
C7H(E)); pq 1.85 (C6H(A), C7H(A)); td 1.81 (C2H(A),
3
4
(500 MHz, CDCl3): δ dd 8.97 (C2”H), J = 4.0, J = 1.5; d
3
3
3
4
C4H(A)), JA–A = 11.5, JA–E = 2.0; 13C NMR (125 MHz,
CDCl3): δ 163.7 (C11); 149.8 (C2”); 149.7 (C2’, C6’);
149.4 (C4’); 146.5 (C8”a); 137.4 (C4”); 130.1 (C8”); 129.6
(C7”); 129.3 (C4”a); 127.8 (C5”); 127.7 (C6”); 123.4 (C3’,
C5’); 118.8 (C3”); 59.3 (C1, C5); 55.4 (C9); 41.4 (C3); 38.4
(C2, C4); 26.6 (C6, C7); IR (KBr) cm−1: ν3277 (NH), 1659
(CO); ESI-HRMS m/z calcd for C23H24N4ONa (M + Na)+
395.1848, found: 395.1835.
8.54 (C2’H, C6’H), J = 5.5; d 8.29 (C5”H), J = 2.0; dd
8.20 (C8”H), 3J = 8.0, 5J = 1.0; d 8.13 (C4”H), 3J = 9.0; dd
3
4
3
8.06 (C7”H), J = 8.5, J = 2.0; dd 7.45 (C3”H), J1 = 8.5,
3J2 = 4.5; d 7.33 (C3’H, C5’H), 3J = 5.5; d 6.52 (NH), 3J =
8.0; m 4.44 (C3H); s 3.56 (C9H2); pt 3.24 (C1H, C5H); m
2.08 (C2H(E), C4H(E)); m 1.99 (C6H(E), C7H(E)); pq 1.82
3
(C6H(A), C7H(A)); td 1.73 (C2H(A), C4H(A)), JA–A
=
12.5, JA–E = 2.5; 13C NMR (125 MHz, CDCl3): δ 166.2
(C11); 151.9 (C2”); 149.6 (C2’, C6’); 149.5 (C4’); 149.3
(C8”a); 136.9 (C5”); 132.7 (C6”); 129.9 (C4”); 127.5
(C4”a); 127.5 (C7”); 127.1 (C8”); 123.3 (C3’, C5’); 121.9
(C3”); 59.4 (C1, C5); 55.5 (C9); 42.0 (C3); 38.6 (C2, C4);
26.5 (C6, C7); IR (KBr) cm−1: ν3277 (NH), 1647 (CO);
ESI-HRMS m/z calcd for C23H24N4ONa (M + Na)+
395.1848, found 395.1832.
3
N-[8-(4-pyridylmethyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-quino-
line-3-carboxamide
(12u) Column
chromatography
chloroform: methanol (95: 5 v/v). Yield: 0.44 g (58.34%);
1
m.p. 69.5–72.0 °C; H NMR (500 MHz, CDCl3): δ C3H
axial conformation: d 9.27 (C2”H), 4J = 2.5; d 8.58
(C4”H), 4J = 2.0; m* 8.54 (C2’H, C6’H); m* 8.14 (C8”H);
d 7.86 (C5”H), 3J = 8.0; m* 7.79 (C7”H); m* 7.60 (C6”H);
m* 7.34 (C3’H, C5’H); d 6.67 (NH), 3J = 8.0; m 4.46
(C3H); s* 3.57 (C9H2); m* 3.25 (C1H, C5H); m 2.09 (C2H
(E), C4H(E)); m 2.00 (C6H(E),C7H(E)); m* 1.84 (C6H(A),
N-[8-(4-pyridylmethyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-4-
methoxyquinoline-2-carboxamide (12w) Column chroma-
tography chloroform: methanol (96: 4 v/v). Yield: 0.40 g

Medicinal Chemistry Research (2018) 27:1906–1928
1917
(49.19%); m.p. 52.0–55.0 °C; 1H NMR (500 MHz, CDCl3):
δ dd 8.55 (C2’H, C6’H), 3J = 4.5, 4J = 1.5; dd 8.22 (C8”H),
3J = 8.5, 4J = 1.5; d 8.17 (NH), 3J = 8.5; d 8.03 (C5”H), 3J
(KBr) cm-1: ν3252 (NH), 1631 (CO), 1551 (C-NO2 asym);
1334 (C-NO2 sym); ESI-HRMS m/z calcd for
C25H25N3O3Na (M + Na)+ 438.1794, found 438.1801.
3
3
4
= 8.5; m 7.73 (C6”H), J1 = 9.0, J2 = 6.5, J = 1.5; s 7.69
3
3
4
(C3”H); m 7.55 (C7”H), J1 = 8.5, J2 = 7.0, J = 1.0; d
N-[8-(3-nitrobenzyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-2-
3
7.36 (C3’H, C5’H), J = 6.0; m 4.39 (C3H(axial)); s 4.12
naphthamide (18b) Crystallisation from anhydrous etha-
1
(OCH3); s 3.60 (C9H2); pt 3.26 (C1H, C5H); m 2.09 (C2H
nol. Yield: 0.97 g (51.3%); m.p. 184.5–185.8 °C; H NMR
(E), C4H(E)); m 1.97 (C6H(E), C7H(E)); pq 1.85 (C6H(A),
(500 MHz, CDCl3): δ s 8.34 (C2’H); s 8.26 (C1”H); dd 8.10
(C4’H), 3J = 8.0, 4J = 1.0; m 7.94–7.80 (C3”H, C4:H,
C”H, C8”H); d 7.69 (C6’H), 3J = 7.5; m 7.54 (C6”H,
C7”H0; t 7.46 (C5’H), J = 7.5; d 6.17 (NH), J = 8.5; m
4.44 (C3H(axial)); s 3.65 (C9H2), bs 3.24 (C1H, C5H); m
3
3
C7H(A)); td 1.81 (C2H(A), C4H(A)), JA–A = 12.5, JA–E
= 2.5; 13C NMR (125 MHz, CDCl3): δ 163.9 (C11); 163.6
(C4”); 151.3 (C2”); 149.7 (C2’, C6’); 149.4 (C4’); 147.5
(C8”a); 130.3 (C7”); 129.1 (C8”); 126.8 (C6”); 123.4 (C3’,
C5’); 122.0 (C4”a); 122.0 (C5”); 97.8 (C3”); 59.3 (C1, C5);
56.1 (C12); 55.3 (C9); 41.5 (C3); 38.2 (C2, C4); 26.6 (C6,
C7); IR (KBr) cm−1: ν3323 (NH), 1670 (CO); ESI-HRMS
m/z calcd for C24H26N4O2Na (M + Na)+ 425.1953, found:
425.1965.
3
3
2.08 (C6H(E), C7H(E)); m 2.00 (C2H(E), C4H(E)); pq 1.83
3
(C6H(A), C7H(A)); td 1.71 (C2H(A), C4H(A)), JA–A
=
12.0, JA–E = 2.0; 13C NMR (125 MHz, CDCl3): δ 166.8
(C11); 148.4 (C3’); 142.6 (C1’); 134.7 (C4”a); 134.4 (C6’);
132.6 (C2”); 131.9 (C8”a); 129.0 (C8”); 128.9 (C5”); 128.4
(C5’); 127.7 (C1”); 127.6 (C4”); 127.2 (C7”); 126.7 (C6”);
123.6 (C3”); 123.2 ()C4’); 121.9 (C2’); 59.2 (C1, C5); 55.8
(C9); 42.0 (C3); 38.7 (C2, C4); 26.5 (C6, C7); IR (KBr) cm
−1: ν3257 (NH), 1637 (CO), 1554 (C–NO2 asym), 1346
(C–NO2 sym); ESI-HRMS m/z calcd for C25H25N3O3Na (M
+ Na)+ 438.1794, found 438.1801.
3
General procedure for synthesis of N-[8-(nitrobenzyl)-8-
azabicyclo[3.2.1]oct-3β-yl)]-2-naphthamides (18a–c)
N-(8-azabicyclo[3.2.1]oct-3β-yl)-2-naphthamide
hydro-
chloride (17) 1.38 g (4.4 mmol), 0.76 g (4.4 mmol) of an
appropriate nitrobenzyl chloride (2-nitrobenzyl chloride for
18a, 3-nitrobenzyl chloride for 18b, 4-nitrobenzyl chloride
for 18c), K2CO3 1.38 g (10.0 mmol) and 100 mg of KI were
suspended in 60 mL of acetone. The reaction mixture was
refluxed with stirring. The reaction time was determined
using TLC. Solvent was removed and the residue was dis-
solved in a mixture of 30 mL of CH3Cl and 30 mL of
water. The aqueous phase was extracted with CH3Cl (2 ×
20 mL). The combined organic extracts were dried with
magnesium sulphate, filtered, and the solvent was evapo-
rated in vacuo. Compounds 18a–c were purified by
crystallisation.
N-[8-(4-nitrobenzyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-2-
naphthamide (18c) Crystallisation from acetone. Yield:
1.32 g (69.8%); m.p. 207.0–208.6 °C;1H NMR (500 MHz,
3
CDCl3): δ s 8.26 (C1”H; d 8.16 (C3’H, C5’H), J = 8.5; m
7.91–7.80 (C3”H, C4”H, C5”H, C8”H); m 7.60–7.50
(C2’H, C6’H, C6”H, C7”H); d 6.17 (NH), 3J = 8.0; m 4.43
(C3H(axial)); s 3.65 (C9H2); ps 3.23 (C1H, C5H); m 2.07
(C6H(E), C7H(E)); m 2.00 (C2H(E),C4H(E)); pq 1.83
(C6H(A), C7H(A)); m 1.70 (C2H(A), C4H(A)); 13C NMR
(125 MHz, CDCl3): δ 166.8 (C11); 148.1 (C4’); 147.0
(C1’); 134.7 (C4”a); 132.6 (C2”); 131.9 (C8”a); 128.9 C2’,
C6’); 128.8 (C8”); 128.4 (C5”); 127.7 (C1”); 127.6 (C4”);
127.2 (C7”); 126.8 (C6”); 123.5 (C3”); 123.5 (C3’, C5’);
59.3 (C1, C5); 55.9 (C9); 42.0 (C3); 38.7 (C2, C4); 26.5
(C6, C7); IR (KBr) cm−1: ν3251 (NH), 1634 (CO), 1555
(C–NO2 asym); 1345 (C–NO2 sym); ESI-HRMS m/z calcd
for C25H25N3O3Na (M + Na)+ 438.1794, found 438.1784.
N-[8-(2-nitrobenzyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-2-
naphthamide (18a) Crystallisation from anhydrous etha-
1
nol. Yield: 1.04 g (55.0%); m.p. 177.7-179.6 °C; H NMR
(500 MHz, CDCl3): δ s 8.24 (C1”H); dd 7.91 (C3’H), 3J =
7.5; m 7.86 (C3”H, C8”H); m 7.81 (C4”H, C5”H); d 7.65
3
(C6’H), J = 7.5; m 7.50–7.58 (C5’H, C6”H, C7”H); td
3
4
3
7.38 (C4’H), J = 8.0, J = 1.0; d 6.07 (NH), J = 8.5; m
General procedure for synthesis of N-[8-(aminobenzyl)-8-
4.39 (C3H(axial)); s 3.83 (C9H2), pt 3.18 (C1H, C5H; m
azabicyclo[3.2.1]oct-3β-yl)]-2-naphthamides (19a–c)
2.05 (C6H(E), C7H(E)); m 1.94 (C2H(E), C4H(E)); pq 1.80
3
(C6H(A), C7H(A)); td 1.60 (C2H(A), C4H(A), JA–A
=
The appropriate N-[8-(nitrobenzyl)-8-azabicyclo[3.2.1]oct-
3β-yl)]-2-naphthamide (18a for 19a, 18b for 19b or 18c for
19c) (0.83 g, 2 mmol) was dissolved in anhydrous ethanol
(150 mL) and catalytically hydrogenated (0.025 g of PtO2,
5 atm of H2, 24 h). The catalyst was filtered off and the
filtrate was evaporated in vacuo to give crude 19a–c as a
white solid.
12.0, JA–E = 2.5; 13C NMR (125 MHz, CDCl3): δ 166.8
(C11); 149.9 (C2’); 135.4 (C4”a); 134.7 (C2”); 132.6 (C1’);
132.3 (C5’); 132.0 (C8”a); 130.5 (C8”); 128.9 (C5”); 128.4
(C1”); 127.7 (C4’, C4”); 127.7 (C6’); 127.6 (C7”); 127.2
(C6”); 126.7 (C3”); 124.3 (C3’); 123.6 (C1’); 59.6 (C1,
C5); 53.6 (C9); 41.9 (C3); 38.7 (C2, C4); 26.6 (C6, C7); IR
3

1918
Medicinal Chemistry Research (2018) 27:1906–1928
N-[8-(2-aminobenzyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-2-
naphthamide (19a) Column chromatography chloroform:
methanol (95: 5 v/v). Yield: 0.76 g (97.9%); m.p.
172.7–173.3 °C; 1H NMR (500 MHz, CDCl3): δ d 8.40
(C1”H); m 7.95–7.90 (C3”H, C8”H); m 7.89–7.85 (C4”H,
C5’); 58.6 (C1, C5); 55.8 (C9); 42.1 (C3); 38.7 (C2, C4);
26.4 (C6, C7); IR (KBr) cm−1: 3330 (NHar), 1638 (CO),
ESI-HRMS m/z calcd for C25H27N3O (M + H)+ 386.2226,
found 386.2232.
3
C5”H); m 7.56–7.49 (C6”H, C7”H); td 7.03 (C4’H), J =
HPLC analysis
4
3
4
8.0, J = 1.5; dd 6.97 (C6’H), J = 7.5, J = 1.5; dd 6.76
3
4
3
4
(C3’H), J = 8.0, J = 1.0; td 6.63 (C5’H), J = 8.5, J =
1.0; bs 4.51 (NH2); m 4.40 (C3H(axial)); s 3.63 (C9H2); bs
3.25 (C1H, C5H); m 2.10 (C6H(E), C7H(E)); m 1.88–1.75
(C2H(E), C4H(E), C6H(A), C7H(A), C2H(A), C4H(A));
13C NMR (125 MHz, CDCl3): δ 168.9 (C11); 147.9 (C2’);
135.9 (C4”a); 133.7 (C2”); 132.7 (C8”a); 130,8 (C6’);
129.8 (C8”); 129.0 (C4’); 128.9 (C5”); 128.7 (C1’); 128.5
(C4”); 128.4 (C7”); 127.4 (C6”); 125.0 (C3”); 124.7 (C1”);
118.9 (C5’); 117.3 (C3’); 59.2 (C1, C5); 55.7 (C9); 43.1
(C3); 38.2 (C2, C4); 27.0 (C6, C7); IR (KBr) cm−1: 3242
(NHar), ν3237 (NH), 1634 (CO), ESI-HRMS m/z calcd for
C25H27N3O (M + Na)+ 408.2052, found 408.2054.
Dionex system was used. The system consisted of a qua-
ternary pump P580, a UVD detector 340 S, a column
thermostat YetStream II Plus (WO Industrial Electronics),
all controlled with Chromeleon software (version 6.01).
Sample injection was performed through Rheodyne injector
valve with a 20 µl sample loop. Chromatographic separa-
tions were carried out using the NUCLEODUR C18
Gravity column (Machery-Nagel), 150 × 4.6 mm, 5 µm and
guard column NUCLEODUR C18 Gravity 5 µm. Mobile
phases consisted of a mixture of 6 mM octane-1-sulphonic
acid sodium salt and MeOH (55: 45) adjusted the pH to 3
with acetic acid. The flow rate of the mobile phase was
0.8 ml/min. The temperature in the column was maintained
at 30 °C. Thanks to the diode array detector, it was possible
to record UV spectra of analysed compounds with absor-
bance maximum at c.a. 236 nm. Detection was carried out at
λ = 236 nm.
N-[8-(3-aminobenzyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-2-
naphthamide (19b) Column chromatography chloroform:
methanol (85: 15 v/v). Yield: 0.75 g (97.3%); m.p.
165.4–166.6 °C; 1H NMR (500 MHz, CDCl3): δ d 8.43
(C1”H; m 7.97–7.91 (C3”h, C8”H); m 7.90–7.85 (C4”H,
3
C5”H); m 7.53 (C6”H, C7”H); t 7.08 (C5’H), J = 8.0; t
Biological tests
6.9.0 (C2’H); dt 6.79 (C6’H), 3J = 8.0; m 6.71 (C4’H), 3J =
8.0, 4J1 = 2.5, 4J2 = 1.0; bs 4.56 (NH2); m 4.49 (C3H
(axial)), s 3.77 (C9H2); s 3.56 (C1H, C5H); m 2.24 (C6H(E),
C7H(E)); m 2.08 (C2H(E), C4H(E)); m 1.97 (C6H(A), C7H
(A)); m 1.91 (C2H(A), C4H(A); 13C NMR (125 MHz,
CDCl3): δ 170.0 (C11); 149.0 (C3’); 135.9 (C4”a); 133.7
(C2”); 132.4 (C8”a); 130.2 (C5’); 19.8 (C8”); 129.0 (C5”);
128.8 (C1’); 128.5 (C4”, C7”); 127.5 (C6”); 125.0 (C1”,
C3”); 120.1 (C6’); 117.4 (C2’); 116.3 (C4’); 60.6 (C1, C5);
56.1 (C9); 41.9 (C3); 36.6 (C2, C4); 26.4 (C6, C7); IR (KBr)
cm−1: 3309 (NHar), ν1636 (CO); ESI-HRMS m/z calcd for
C25H27N3O (M + Na)+ 408.2052, found 408.2049.
Radioligand binding assay
All compounds were tested for their affinities for 5-HT1A, 5-
HT2A, and D2 receptors according to previously described
procedures (Stefanowicz et al. 2016).
In vivo studies
Animals The experiments were performed on male mice
(22–26 g, Albino Swiss or CD-1). All animals were kept
in an environmentally controlled rooms (ambient tem-
perature 21 2 °C; relative humidity 50–60%; 12:12
light–dark cycle, lights on at 8:00) and filtered water were
freely available. All the experimental procedures were
approved by the I Local Ethics Commission at the
Jagiellonian University in Krakow. All the experiments
were conducted in the light phase between 09:00 and
14:00 h. Each experimental group consisted of 6–10 ani-
mals/dose, and the animals were used only once in each
test.
N-[8-(4-aminobenzyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-2-
naphthamide (19c) Yield: 0.76 g (98.5%); m.p.
201.6–208.8 °C; 1H NMR (500 MHz, CDCl3): δ s 8.22
(C1”H); m 7.86–7.81 (C3”H, C4”H, C8”H); dd 7.79
3
(C5”H), J = 8.5,4J = 1.5; m 7.53 (C6”H, C7”H); d 7.16
3
3
(C2’H, C6’H), J = 8.5; d 6.65 (C3’H, C5’H), J = 8.5; d
3
6.12 (NH), J = 8.5; m 4.42 (C3H(axial)); bs 3.61 (NH2); s
3.45 (C9H2); bs 3.28 (C1H, C5H); m 2.07 (C6H(E), C7H
(E)); m 1.95 (C2H(E), C4H(E)); pq 1.78 (C6H(A), C7H
(A)); td 1.66 (C2H(A), C4H(A)), 3JA–A = 12.0, 3JA–E = 2.0;
13C NMR (125 MHz, CDCl3): δ 166.7 (C11); 145.3 (C4’);
134.6 (C4”a); 132.6 (C2”); 132.1 (C8”a); 129.8 (C2’, C6’);
129.6 (C1’); 128.9 (C8”); 128.4 (C5”); 127.7 (C4”); 127.5
(C7”); 127.2 (C6”); 126.7 (C3”); 123.6 (C1”); 115.0 (C3’,
Spontaneous locomotor activity
The locomotor activity was recorded with an Opto M3
multi-channel activity monitor (MultiDevice Software
v.1.3, Columbus Instruments). The investigated compounds

Medicinal Chemistry Research (2018) 27:1906–1928
1919
or vehicle were administered intraperitoneally (i.p.) 60 min
before the test running. The mice were individually placed
in plastic cages (22 × 12 × 13 cm) for 30 min habituation
period, and then the crossings of each channel (ambulation)
were measured every 5 for 60 min (in CD-1 mice) and
during 1-min or 3–6 min test session for Albino Swiss mice.
The cages were cleaned up with 70% ethanol after each
mouse.
Results and discussion
Chemistry
Final compounds 12a–w and 19a–c were obtained via a
multi-step synthesis according to Scheme 1 and Scheme 2.
The starting compounds (1–9, 13–17) were synthesised
according to procedures described in our previous paper
(Słowiński et al. 2011; Stefanowicz et al. 2016). The 8-
benzyl-8-azabicyclo[3.2.1]oct-3β-yl-amine (7) required for
synthesis of the final compounds were obtained in several
steps. The starting 8-benzyl-8-azabicyclo[3.2.1]octan-3-one
(5) were synthesised from the benzyl amine via a modified
Robinson condensation (Dostert et al. 1984). The obtained
ketone (5) was subsequently converted to an oxime (6),
which was then subjected to a stereoselective reduction with
sodium in butanol to give the equatorial (β) 8-benzyl-8-
azabicyclo[3.2.1]oct-3β-yl-amine (7). The above reactions
were carried out using methods described in the literature
(Dostert et al. 1984). The 8-benzyl-8-azabicyclo[3.2.1]oct-
3β-yl-acetamide (8) were synthesised by the acylation of
compound 7 by treatment with acetyl chloride in the pre-
sence of triethylamine as a base and dichloromethane as a
solvent (Dostert et al. 1984). The N-[8-aryl-8-azabicyclo
[3.2.1]oct-3β-yl]acetamide derivatives (10a–f) were
obtained from the known intermediate 8-azabicyclo[3.2.1]
oct-3β-yl-acetamide hydrochloride 9, via debenzylation to
amide 8, which was then alkylated with the appropriate
benzylmethyl chloride or pyridinemethyl chlorides using
the Finkelstein protection of KI (Scheme 1). Compounds
10a–f have not been described before in the literature.
The next stage was acid catalysed hydrolysis of the
amide bond of 10a–f derivatives, giving 8-aryl-8-azabicyclo
[3.2.1]oct-3β-yl-amine derivatives (11a–f). Due to the high
process yield and purity of the crude products, compounds
11a–f were used in subsequent reactions without further
purification. The mixed anhydride method was used in
order to obtain the final planned β-quinolineamide deriva-
tives (12a–w).
MK-801-induced hyperactivity
MK-801-induced hyperactivity in mice was recorded
according to the method described above. The investigated
compounds or vehicle were administered i.p. 30 min., while
MK-801 0.2 mg/kg i.p. 15 min before the test running.
Amphetamine-induced hyperactivity
d-Amphetamine-induced hyperactivity in mice was recor-
ded according to the method described above. The inves-
tigated compounds or vehicle were administered i.p., while
amphetamine 2.5 mg/kg subcutaneously (s.c.) 30 min before
the test running.
Forced swim test in mice
The experiment was carried out according to the method of
Porsolt et al. (1979). Mice (Swiss Albino) were individually
placed in a glass cylinder (25 cm high; 10 cm in diameter)
containing 10 cm of water maintained at 23–25 °C, and
were left there for 6 min. A mouse was regarded as
immobile when it remained floating on the water, making
only small movements to keep its head above it. The total
duration of immobility was recorded during the last 4 min of
a 6-min test session.
Four-plate test in mice
Test was performed on male Swiss Albino mice. A single
mouse was placed gently onto the plate, and each animal was
allowed to explore for 15 s. Afterwards, each time a mouse
passed from one plate to another, the experimenter electrified
the whole floor for 0.5 s (current 0.8 mA), which evoked a
visible flight reaction of the animal. If the animal continued
running, it received no new shock for the following 3 s. The
number of punished crossings was counted for 60 s.
All except one of the reported synthesis methods for the
final compounds proved to be stereospecific. However,
compound 12u was obtained as a mixture of isomers (see
Scheme 1). This observation is of particular interest in view
of earlier our research results of group 3β-acylamine deri-
vatives of tropane. The ratio of 12u isomers in the mixture
1
was confirmed by H NMR and HPLC spectral analysis as
described in section Conformational analysis.
Statistical analysis
The synthesis of N-[8-(aminobenzyl)-8-azabicyclo[3.2.1]
oct-3β-yl)]-2-naphthamide derivatives (19a–c) were
accomplished according to Scheme 2. The N-(8-azabicyclo
The data are presented as the mean S.E.M.The obtained
data were analysed by one-way analysis of variance
(ANOVA) followed by Bonferroni’s post-hoc test. p < 0.05
were considered statistically significant.
[3.2.1]oct-3β-yl)-2-naphthamide
hydrochloride
(17)
required for synthesis of the final compounds were obtained
from the known intermediate N-(8-methyl-8-azabicyclo

1920
Medicinal Chemistry Research (2018) 27:1906–1928
[3.2.1]oct-3β-yl)-2-naphthamide (16) via demethylation
with Olofson’s reagent. The above reactions were carried
out using methods described in our previous paper (Stefa-
nowicz et al. 2016). Next, 17 was alkylated with the
appropriate nitrobenzyl chlorides to give the corresponding
N-[8-(nitrobenzyl)-8-azabicyclo[3.2.1]oct-3β-yl)]-2-naph-
thamides derivatives (18a–c). In the next stage, appropriate
18a–c derivatives were subjected to catalytic hydrogenation
of the nitro group in the presence of PtO2 to give final
compounds 19a–c.
C4H. This assumption cannot hold for the 14-line pre-
sentation and it can be assumed in this latter case that the
signal from the C3H proton is split into a triplet by coupling
with the axial C2H and C4H protons, followed by a split of
the triplet components into doublets by the NH proton and,
finally, followed by the components of the three doublets
being split by equatorial C2H and C4H protons. As a result
there are 18 theoretical lines, but partial signal overlap
simplifies the multiplet to 14 lines, confirming our
assumption that the C3H proton is axial, but also leading to
the conclusion that the spatial position of the equatorial
-NH-CO-R substituent is different in the different com-
pounds analysed (Figs. 4 and 5).
The structures of all novel intermediates and final com-
1
pounds were confirmed by IR, H NMR and 13C NMR
spectroscopy and ESI-HRMS spectrometry. Detailed char-
acterisation data are provided in Material and methods
section. For in vivo and in vitro investigations, free bases
were converted into the corresponding water-soluble salts.
An unexpected effect is seen in the spectra of sample
12u, where there is a marked increase in the number of
1
signals in the 13C and H NMR spectra, suggesting the
presence of a mixture of compounds. Fortunately, the
finding of distinct multiplets of the C3H proton (in the
proton spectrum) allows the conclusion that there is a
mixture of two isomers: one (β) with an axial multiplet of
the C3H proton (12 lines) and one (α) with an equatorial
multiplet of the C3H proton (4 lines). Apparently, the
equatorial C3H proton couples with three protons, namely,
the axial C2H and C4H, and NH to produce a pseudo-
quartet. This requires making the assumption that the cou-
pling constant for C2H and C4H equals 0. Then (according
to the Karplus curve), the C3H coupling plane forms an
angle of ~90o with the coupling planes of C2H and C4H.
Conformational analysis
1
The H and 13C NMR spectra of the samples 12a–w con-
firm the assumed structures (see Material and methods
section). The signal of the C3H proton (in proton spectra) is
particularly interesting as it has the form of a 12-line or 14-
line multiplet. In order to account for this splitting pattern
we need to assume that the C3H proton is axial. For the 12-
line presentation, we can assume that the multiplet is
formed of 3 overlapping quartets, this corresponding to an
initial split into a triplet by axial C2H and C4H protons
followed by the triplet constituents splitting into quartets as
a result of coupling with the three protons of C2H and C4H
(equatorial) and NH. We assume that the NH proton cou-
pling constant is the same as (or very similar to) the con-
stants of coupling to the equatorial protons of C2H and
1
Integrals (in H NMR spectra) can be used to calculate that
the molar ratio of the β form to the α form is 2:1. This
conclusion is corroborated by a good fit of the chemical
shifts in 1H and 13C NMR spectra with the spectra of similar
structures.
12u, 0,1mg/ml, 0,8ml/min, 30°C , 6mM, octanesulfonate: MeOH 55:45
UV_VIS_1
WVL:236 nm
350
5 - isomer beta - 17,656
200
4 - isomer alpha - 14,131
100
3 - 8,461
2 - 7,483
1 - 5,025
6,0
-50
0,0
2,0
4,0
8,0
10,0
12,0
14,0
16,0
18,0
20,0
22,0
25,0
Fig. 4 Chromatogram of 12u (mixture of stereoisomers α and β)

Medicinal Chemistry Research (2018) 27:1906–1928
1921
12m ,0,1mg/ml ,0,8ml/min, 30°C, 6mM, octanesulfonate: MeOH 55:45
UV_VIS_1
WVL:236 nm
300
250
200
150
100
50
4 - isomer beta - 22,747
3 - isomer alpha - 18,283
1 - 1,849
2,5
2 - 5,026
-20
0,0
5,0
7,5
10,0
12,5
15,0
17,5
20,0
22,5
25,0
27,5
29,7
Fig. 5 Chromatogram of 12m (mixture of stereoisomers α and β)
HPLC studies were conducted following determination
of NMR spectra, which revealed that 12u is a mixture of
stereoisomers. The synthesis was repeated twice, with
HPLC analysis producing very similar results to NMR
spectral analysis.
Biological evaluation
Radioligand binding assay for D2, 5-HT1A, and 5-HT2A
receptors
The UV spectra (see supplementary material) are iden-
tical and characterised by the same absorbance maximums;
i.e., at wavelengths equal to their absorbance maximum,
both isomers are detected at the same maximum sensitivity.
In this situation, the mass ratio of the isomers can be
determined by comparing peak areas.
The peak area for 12u α, at tR = 14.131 min., is
125.1019 mAU × min., compared to 300.2409 mAU × min
for 12u β, at tR = 17.656 min., producing an α:β ratio of
1:2.4, corresponding to an approximately 29.4% admixture
of the 12u α isomer.
As mentioned in the Introduction, ligands with simulta-
neous affinity for D2, 5-HT1A, and 5-HT2A receptors seem to
be promising compounds for the pharmacotherapy of schi-
zophrenia. In our previous paper, we described the synthesis
and biological evaluation of compounds with very good
double binding to D2 and 5-HT2A receptors; the most potent
are shown in Fig. 1. Thus, in the subsequent phase of
experimentation, we focused our attention on evaluating the
impact of lead structure modification on 5-HT1A receptor
affinity. Therefore, the compounds synthesised within the
present project included structural analogues of 3β-acyla-
mine derivatives of tropane with the introduction of a
methyl substituent in the benzyl ring and a quinoline moi-
ety. These modifications were designed as a result of pre-
vious research, aiming to develop new ligands with
enhanced 5-HT1A binding activity in the investigated group
of tropane derivatives.
Compounds 12a–w and 19a–c were tested for their
in vitro affinity for the D2, 5-HT1A, and 5-HT2A receptors
using a radioligand binding assay. Competition binding
studies were performed according to a previously described
procedure in rat brain tissues (Stefanowicz et al. 2016). The
results are presented in Table 1.
First, the impact of structure modifications to the qui-
noline derivatives (12a–w) on D2 affinity were examined.
The influence of the quinoline moiety and its derivatives
were analysed. The nitrogen position in the quinolinyl
fragment impacted on the affinity for D2. We observed the
To check for stereochemical purity, the analysis was
repeated for the remaining compounds. This paper contains
the results for the compound 12m. The area of the 12m α
peak, at tR = 18.283 min., is 2.0553 mAU × min., and the
area of the 12m
β peak, at tR = 22.747 min., is
300.1300 mAU × min., producing an α:β ratio of 1:146,
which corresponds to an admixture of the 12m α isomer of
approximately 0.7%.
In summary, all target compounds are equatorial isomers
(3β), except for the derivative 12u. To our surprise, the
admixture of an axial isomer (3α) was significant (29.4% by
HPLC) only in this case. The same results were seen with
the re-synthesised compound. We are unable to account for
this isomerisation, the less so as the analogues 12t, 12v, and
12w obtained from the same stereochemically pure sub-
strate 10f (NMR) are stereochemically pure equatorial iso-
mers. Work to explain this is under way.

1922
Medicinal Chemistry Research (2018) 27:1906–1928
Table 1 Binding affinities for dopamine D2 and serotonin 5-HT1A/5-HT2A receptors

Medicinal Chemistry Research (2018) 27:1906–1928
1923

1924
Medicinal Chemistry Research (2018) 27:1906–1928
Table 2 Effects of 12e, 12i, and 19a on the MK-801-induced
hyperlocomotor activity in CD-1 mice
same rank order: 2-quinolinyl > 6-quinolinyl > 3-quinolinyl
in the case of all ligands. Therefore, introduction of 2-
quinoline fragment in ligands was found to be favourable
for D2 binding, with the highest affinity seen for
compound 12i. At the same time, the 4-methoxy-quinoline
analogues had in general the lowest affinity for this
receptor.
Treatment
Dose (mg/ Number of crossings/60 min
kg)
Mean SEM
Control
0
3243.3 519.8
MK-801
0.2
6329.9 1012.5; p < 0.05 vs. contr
12e + MK- 0.625 +
4375.1 583.4; ns, ns
Next, by comparing the influence the location of the
methyl substitution in the benzyl ring, it was confirmed that
p-substituted ligands (12i, 12j, 12k) were considerably
more potent than their m-substituted or o-substituted ana-
logues, with compound 12i (p-CH3) displaying a D2 Ki =
7.4 nM. This is in accordance with our previous results
(Stefanowicz et al. 2016).
801
0.2
1.25 + 0.2 4019.3 341.3; ns, ns
2.5 + 0.2
5 + 0.2
5440.1 937.3 ns, ns
3580.7 384.9; ns, ns
F(5,48) = 2.8885; p < 0.05
Control
0
2362.7 400.8
MK-801
0.2
4708.1 522.1; p < 0.01 vs. contr
The substitution of a 2-piridylmethyl, 3-piridylmethyl, or
4-piridylmethyl at the in N8 position resulted in a sig-
nificant loss of activity at the D2 receptor.
12i + MK- 5 + 0.2
801
2432.8 526.6; ns vs. contr
p < 0.01 vs. MK
10 + 0.2
805.4 147.2 ns vs. contr
p < 0.0001 vs. MK
Analysing the Ki values for 5-HT1A receptors, we found
that the introduction of quinoline and its derivatives was
beneficial in terms of 5-HT1A receptor binding affinity.
Furthermore, the presence of the 4-methoxy-2-quinoline
moiety notably ameliorated the affinity for the 5-HT1A
receptor. This enhancing effect was greatest for compound
12h Ki = 21.0 nM. The nitrogen position in the quinolinyl
fragment also affected binding to 5-HT1A receptors; these
could be ranked in order of their increasing influence as
follows: 2-quinolinyl > 3-quinolinyl > 6-quinolinyl.
After analysis of the results obtained in the radioligand
binding assay, it was concluded that very high affinity for
the 5-HT1A receptor was demonstrated by the following
ligands: 12a (Ki = 46.6 nM), 12d (Ki = 34.0 nM), 12h (Ki
= 21.0 nM), 12i (Ki = 43.5 nM). Taking into consideration
the impact of o-methyl, m-methyl, or p-methyl substituents
located in the benzyl ring on affinity for the 5-HT1A
receptor, it can be stated that the substituents generally did
not have a significant effect on affinity compared to the non-
substituted analogues. The o-methyl, m-methyl, or p-methyl
benzyl with 2-quinolinyl moiety derivatives showed
good binding affinity, especially 12a (Ki = 46.6 nM), 12e
(Ki = 55.3 nM), and 12i (Ki = 43.5 nM), compared to the
corresponding non-substituted analogue N-(8-benzyl-8-
azabicyclo[3.2.1]oct-3b-yl)-quinoline-2-carboxamide (Ki =
62.7 nM). As well, the 5-HT1A receptor affinity of the
substituted 4-methoxy quinolinyl analogues 12d (Ki =
34.0 nM) and 12h (Ki = 21.0 nM) can be compared to the
corresponding non-substituted analogue N-(8-benzyl-8-
azabicyclo[3.2.1]oct-3b-yl)-4-methoxyquinoline-2-carbox-
amide (Ki = 30.5 nM).
F(3,30) = 14.206; p < 0.0001
Control
0
1629.7 235.6
MK-801
0.2
6247.1 1063.8; p < 0.01 vs. contr
19a + MK- 1.25 + 0.2 4646.4 675.6; ns, ns
801
2.5 + 0.2
3832.0 991.3; ns, ns
F(3,33) = 5.2088; p < 0.01
Control
0
2068.3 387.3
MK-801
0.2
8757.9 1378; p < 0.00001 vs. contr
19a + MK- 5 + 0.2
801
2915.4 580.2; p < 0.001 vs. MK; ns vs.
contr
F(2,27) = 16.679; p < 0.0001
Control
0
2362.7 400.8
MK-801
0.2
4708.1 522.1; p < 0.01 vs. contr
19a + MK- 10 + 0.2
801
808.7 66.3; p < 0.0001 vs. Mk; p < 0.05
vs. contr
F(2,20) = 23.813; p < 0.001
The investigated compounds were injected i.p. 30 min, while MK-801
15 min. before the test. Values represent the mean SEM during 60-
min test session compared to the respective group (one-way ANOVA
is followed by the Bonferroni’s post hoc test), N = 8–10, NS–non-
significant
It is worth mentioning that the replacement of the
naphthyl ring with heterocyclic analogues led to the com-
plete loss of 5-HT2A receptor affinity in the investigated
group of ligands. Thus, the presence of a naphthyl moiety is
crucial for obtaining ligands in this series with triple binding
activity for the D2, 5-HT1A, and 5-HT2A receptors.
The introduction of an additional nitrogen atom into the
molecule as an amine group in the phenyl ring (Fig. 2) in
derivatives 19a-c resulted in a marked increase in affinity
for all receptors under study. The resulting compounds
showed the highest binding affinity for the D2, 5-HT1A, and
5-HT2A receptors of all derivatives described in this paper.
In this respect, the compound 19a (Ki[nM] = D2 = 41.5; 5-
HT1A = 53.0; 5-HT2A = 46.8) appears to hold the greatest
In contrast 2-pyridine, 3-pyridine, or 4-pyridine deriva-
tives (12l-w) displayed dramatically lower binding affinity
for 5-HT1A receptors than their benzene substituted ligands.
The highest affinity was observed for the 2-pyridine ana-
logue 12o (Ki = 151.0 nM).

Medicinal Chemistry Research (2018) 27:1906–1928
1925
Table 3 Effects of 12e, 12i, and 19a on the d-amphetamine-induced hyperlocomotor activity in CD-1 mice
Treatment
Dose (mg/kg)
Number of crossings/60 min
Mean SEM
Control
0
2011.7 358.8
d-amphetamine
12e + d-amphetamine
2.5
6553.1 1214.5; p < 0.001 vs. contr
2.5 + 2.5
5 + 2.5
10 + 2.5
2993.0 301.0; p < 0.01 vs. amph.; ns vs. contr
2651.0 512.6; p < 0.01 vs. amph.; ns vs. contr
909.9 11.3; p < 0.0001 vs. amph.; ns vs. contr
F(4,42) = 10.584; p < 0.0001
Control
0
2664.2 540.9
d-amphetamine
12i + d-amphetamine
2.5
6819.9 1534.7; p < 0.05 vs. contr
1771.3 470.4; p < 0.01 vs. amph.; ns vs. contr
5 + 2.5
10 + 2.5
2046.2 63.1; p < 0.01 vs. amph.; ns vs. contr
F(3,34) = 6.5110; p < 0.01
Control
0
2664.2 540.9
d-amphetamine
19a + d-amphetamine
2.5
6819.9 1534.7; p < 0.05 vs. contr
4328.6 1146.8
5 + 2.5
10 + 2.5
950.0 411.7; p < 0.01 vs. amph.; ns vs. contr
F(3,35) = 5.6910; p < 0.01
The investigated compounds were injected i.p., while d-amphetamine s.c., 30 min. before the test. Values represent the mean SEM during 60-min
test session compared to the respective group (one-way ANOVA is followed by the Bonferroni’s post hoc test), N = 8–10, NS–non-significant
Table 4 Effects of 12e, 12i, and 19a on the spontaneous locomotor
the o-isomer was the most active one and the p-isomer was
activity in CD-1 mice
the least active. Of note, unlike the other new structures,
Treatment
Dose (mg/kg)
Number of crossings/60 min
Mean SEM
these three compounds are naphthalene derivatives. This
again seems to lead to the conclusion that the presence of a
naphthalene system in these compounds is more beneficial
than the presence of a quinoline system in terms of pro-
ducing a derivative with triple binding affinity for the D2, 5-
HT1A, and 5-HT2A receptors. The salts of compounds 19a–c
were also characterised by the best solubility in water
among all the derivatives analysed.
In summary, the introduction of an additional nitrogen
atom into the naphthalene or phenyl ring had an overall
adverse effect on the binding affinities of the new com-
pounds compared to the lead structure (compound A) and
its derivatives described in our previous publication. This
modification had the greatest negative effect on affinity for
the 5-HT2A receptor. Of note, the 2-quinoline derivatives
12e and 12i demonstrated very good binding affinity for the
D2 and 5-HT1A receptors, being superior in this respect to
the 3- and 6-quinoline analogues.
Control
0
3352.9 966.4
12e
10
1034 255.9 p < 0.05
F(1,18) = 5.4398; p < 0.05
Control
0
1280.2 222.2
12i
1.25
2.5
5
1573.6 149.3
2676.0 336.7; p < 0.01
1135.8 184.3
F(3,34) = 8.8733; p < 0.001
Control
0
2068.3 387.3
2467,9 539.3
19a
1,25
2,5
1634.4 511.9
F(2,27) = 0.7417; NS
Control
0
1280.2 222.2
1480.4 302.3
19a
5
10
491.6 126.5
F(2,26) = 5.3557; p < 0.05
The introduction of a pyridine ring into the molecule had
an adverse effect on binding affinity, while the introduction
of an amine group as a substituent in the phenyl ring pro-
duced very active compounds. Compound 19a is excep-
tional among the analysed structures as it demonstrates
comparable affinities for all three receptor types (D2, 5-
HT1A, and 5-HT2A), resulting in a very quetiapine-like
receptor profile, but with binding affinities 4-fold or 5-fold
higher than those of quetiapine.
The compounds were injected i.p. 30 min, before the test. Values
represent the mean SEM during 60-min test session compared to the
respective vehicle group (one-way ANOVA is followed by the
Bonferroni’s post hoc test), N = 8–10, NS–non-significant
promise. The affinity of the derivative 19a described above
and its analogues 19b and 19c was markedly influenced by
the position of the -NH2 moiety in the benzyl system, where

1926
Medicinal Chemistry Research (2018) 27:1906–1928
Table 5 Effects of 12d, 12e, 12h, 12i, and 19a in the forced swim test
Table 6 Effects of 12d, 12e, 12h, 12i, and 19a in the four-plate test in
in Albino Swiss mice
Albino Swiss mice
Treatment
Dose (mg/kg)
Immobility time (s)
Mean SEM
Treatment
Dose (mg/kg)
Number of punished crossings /1 min
Mean SEM
Control
0
142.10 8.9
144.22 14.5
113.44 14.9
Control
0
3.3 0.2
3.3 0.3
4.8 0.3
12d
1.25
2.5
5
12d
2.5
5
150.8 11.4
10
4.7 0.8
F(3,32) = 5.5680; NS
F(3,36) = 3.1652; p < 0.05
Control
0
183.56 12.4
172.14 11.6
15.44 16.8
Control
0
3.3 0.2
3.5 0.3
2.9 0.3
12e
2.5
5
12e
2.5
5
10
183.33 12.3
10
3.8 0.5
F(3,30) = 1.2074; NS
F(3,36) = 1.3827; NS
Control
0
142.10 8.9
163.29 10.7
134.78 12.9
Control
0
3.3 0,2
12h
0.625
1.25
2.5
12h
1.25
2.5
5
5.3 0.3; p < 0.001
5.5 0.5; p < 0.001
185.00 15.0
2.9 0.3
F(3,30) = 3.5680; p < 0.05
F(3,36) = 17.202; p < 0.00001
Control
0
157.33 16.1
132.00 2.93
149.89 12.7
Control
0
3.6 0.5
3.1 0.3
2.3 0.4
12i
1.25
2.5
5
12i
2.5
5
219.67 1.43; p < 0.05
10
1.7 0.4; p < 0.05
F(3,26) = 7.5750; p < 0.001
F(3,35) = 4.2954; p < 0.05
Control
0
168.50 5.9
120.00 16.6
128.89 12.3
Control
0
2.8 0.5
3.2 0.5
1.1 0.2
19a
1.25
2.5
5
19a
2.5
5
96.56 16.2; p < 0,01
10
3.2 0.5
F(3,31) = 4.5279; p < 0.01
F(3,33) = 5.6670; p < 0.01
Control
–
162.71 6.8
Control
–
4.2 0.4
Imipramine
5
170.42 10.9
Diazepam
1.25
2.5
5
5.8 0.3; p < 0.01
6.4 0.5; p < 0.01
10
20
119.63 13,0; p < 0.05
77.81 12.2; p < 0.001
6.6 0.4; p < 0.05
F(3,36) = 16.7570; p < 0.0001
F(3,36) = 6.455; p < 0.01
The compounds were injected i.p. 30 min. before the test. Values
represent the mean SEM during last 4-min test session compared to
the respective vehicle group (one-way ANOVA is followed by the
Bonferroni’s post hoc test), N = 6–9, NS–non-significant
The investigated compounds were injected i.p. 30 min., while
diazepam 60 min. before the test. Values represent the mean SEM
during 1-min test session compared to the respective vehicle group
(one-way ANOVA is followed by the Bonferroni’s post hoc test), N =
8–10, NS–non-significant
In vivo studies
hyperlocomotor activity test in mice were carried out.
Compounds 12i (5 mg/kg and 10 mg/kg i.p.), 19a (5 mg/kg
and 10 mg/kg i.p.) significantly reduced MK-801-induced
hyperlocomotor activity (Table 2). Compound 12e admi-
nistered at a dose of 5 mg/kg showed a tendency to decrease
the MK-801-induced hyperlocomotor activity but the results
did not reach a statistically significant level (Table 2). In d-
amphetamine-induced hyperlocomotor activity test, com-
pounds 12i and 12e (at doses of 5 and 10 mg/kg i.p.) sig-
nificant decreased locomotor hyperactivity in the range of
60–86% vs. respective d-amphetamine group (Table 3). The
compound 19a was active in this test only at a dose of
10 mg/kg i.p. (Table 3).
General Experiments were carried out on Albino Swiss or
CD-1 male mice weighing 22–26 g kept in colony cages in
standard laboratory conditions. Experimental groups were
chosen randomly and each animal was used only once. The
compounds studied were suspended in a 1% solution of
Tween 80 (Sigma, St. Louis, MO, USA) and injected
intraperitoneally in a volume of 10 ml/kg.
Antipsychotic-like activity
To study the potential antipsychotic activity of selected
compounds the d-amphetamine- and MK-801-induced

Medicinal Chemistry Research (2018) 27:1906–1928
1927
The compounds 19a (10 mg/kg) and 12i (10 mg/kg)
significantly decreased spontaneous locomotor activity
about 70% since the positive effects observed in hyperlo-
comotor activity tests may not be specific (Table 4). The
compound 12e at the doses used in hyperlocomotor activity
tests did not change the spontaneous locomotor activity in
mice, thus its antipsychotic-like effect appeared to be spe-
cific (Table 4).
Studies of behavioural activity of selected compounds
(12d, 12e, 12h, 12i, and 19a) showed that the compounds
12i and 19a exerted a specific antipsychotic-like effect in d-
amphetamine-induced and MK-801-induced hyperloco-
motor activity test in mice. Specific antidepressant-like
activity (the forced swim test) was displayed only by the
compound 19a and a specific anxiolytic-like effect was
produced only by 12h (Figs. 3–5).
The beneficial and more comprehensive activity profile
of the compound 19a encourages further rational search for
new antipsychotics with an affective component in this
structural class.
Antidepressant-like activity
The potential antidepressant activity of selected compounds
in vivo was investigated using the forced swim test in mice.
In this test only compound 19a (5 mg/kg i.p.) decreased
immobility time about 43% vs. respective control group,
showing significant antidepressant-like activity (Table 5).
Acknowledgements Behavioral studies were partially financed by
Jagiellonian University Medical College funds for statutory activity
(K/ZDS/006133). The authors would like to acknowledge Agata
Siwek and Gabriela Starowicz from Jagiellonian University in Krakow
for the radioligand binding assay.
Anxiolytic-like activity
Compliance with ethical standards
The potential anxiolytic activity of selected compounds
in vivo was investigated using the four-plate test in mice. In
this test only compound 12h (1.25 and 2.5 mg/kg i.p.)
increased punished crossings in a range of 60% vs.
respective control group, showing significant anxiolytic-like
activity (Table 6).
Active doses of the investigated compounds had no
influence on the spontaneous locomotor activity measured
during the time equal to the observation period in the forced
swim and the four-plate tests (i.e., from 2–6 min and 1 min
15 s, respectively) (data not shown) thus observed
antidepressant-like and/or anxiolytic-like activity of these
compounds seems to be specific.
Conflict of interest The authors declare that they have no conflict of
interest.
Open Access This article is distributed under the terms of the Creative
Commons Attribution 4.0 International License (http://crea
tivecommons.org/licenses/by/4.0/), which permits use, duplication,
adaptation, distribution, and reproduction in any medium or format, as
long as you give appropriate credit to the original author(s) and the
source, provide a link to the Creative Commons license, and indicate if
changes were made.
References
Citrome L (2015) The ABC’s of dopamine receptor partial agonists-
Aripiprazole, brexpiprazole and cariprazine: The 15-min chal-
lenge to sort these agents out. Int J Clin Pract 69:1211–1220
Creese I, Burt D, Snyder S (1976) Dopamine receptor binding predicts
clinical and pharmacological potencies of antischizophrenic
drugs. Science 192:481–483
Conclusion
Davis KL, Kahn RS, Grant K, Davidson M (1991) Dopamine in
Schiziophrenia, a review and reconceptualization. Am J Psy-
chiatry 148:1474–1486
Dostert P, Imbert T, Langlois M et al. (1984) Studies on the neuro-
leptic benzamides. III-Synthesis and antidopaminergic properties
of new 3-nortropane derivatives. Eur J Med Chem-Chim Ther
19:105–110
Frankel JS, Schwartz TL (2017) Brexpiprazole and cariprazine: dis-
tinguishing two new atypical antipsychotics from the original
dopamine stabilizer aripiprazole. Ther Adv Psychopharmacol
7:29–41
Haleem DJ (2015) 5-HT1A receptor-dependent control of nigrostriatal
dopamine neurotransmission in the pharmacotherapy of Parkin-
son’s disease and schizophrenia. Behav Pharmacol 26:45–58
Howes OD, Kapur S (2009) The dopamine hypothesis of schizo-
phrenia: version III-The final common pathway. Schizophr Bull
35:549–562
We have described here a series of 26 compounds repre-
senting new derivatives of 3β-aminotropane and being
analogues of a previously identified compound A, which
shows high activity at the D2, 5-HT1A, and 5-HT2A recep-
tors. Modifications involved the introduction of an addi-
tional nitrogen atom, producing quinoline, isoquinoline or
pyridine derivatives or derivatives with an amine group as a
substituent in the phenyl ring (Fig. 2). Structure-activity
relationship studies revealed that these modifications
adversely affected the binding affinity of these compounds
for the three types of receptors, except for the derivatives
12e and 12i, which demonstrated high binding affinity for
the D2 and 5-HT1A receptors, and the compound 19a, which
showed comparable binding affinities for all three receptor
types (D2, 5-HT1A, and 5-HT2A), giving it a very quetiapine-
like receptor profile, but with 4-fold or 5-fold higher bind-
ing affinities than that antipsychotic drug.
Howes OD, McCutcheon R, Owen MJ, Murray RM (2017) The role of
genes, stress, and dopamine in the development of schizophrenia.
Biol Psychiatry 81:9–20

1928
Medicinal Chemistry Research (2018) 27:1906–1928
Meltzer HY (2013) Update on typical and atypical antipsychotic drugs.
Annu Rev Med 64:393–406
Meltzer HY, Huang M (2008) In vivo actions of atypical antipsychotic
drug on serotonergic and dopaminergic systems. Prog Brain Res
172:177–197
Meltzer HY, Massey BW (2011) The role of serotonin receptors in the
action of atypical antipsychotic drugs. Curr Opin Pharmacol
11:59–67
Meltzer HY, Matsubara S, Lee JC (1989) Classification of typical and
atypical antipsychotic drugs on the basis of dopamine D-1, D-2
and serotonin2 pKi values. J Pharmacol Exp Ther 251:238–246
Möller D, Salama I, Kling RC et al. (2015) 1,4-Disubstituted aromatic
piperazines with high 5-HT2A/D2 selectivity: quantitative
structure-selectivity investigations, docking, synthesis and bio-
logical evaluation. Bioorg Med Chem 23:6195–6209
Neves G, Menegatti R, Antonio CB et al. (2010) Searching for multi-
target antipsychotics: discovery of orally active heterocyclic N-
phenylpiperazine ligands of D2-like and 5-HT1A receptors. Bioorg
Med Chem 18:1925–1935
Newman-Tancredi A, Albert PR (2012) Gene polymorphism at ser-
otonin 5-HT1A receptors: moving towards personalized medicine
for psychosis and mood deficits? In: Sumiyoshi T (ed) Schizo-
phrenia Research: Recent Advances. Nova Science Publishers
Inc., New York, p 339–360
Stefanowicz J, Słowiński T, Wróbel MZ et al. (2016) Synthesis and
biological investigation of new equatorial (β) stereoisomers of 3-
aminotropane arylamides with atypical antipsychotic profile.
Bioorg Med Chem 24:3994–4007
Sumiyoshi T, Kunugi H, Nakagome K (2014) Serotonin and dopamine
receptors in motivational and cognitive disturbances of schizo-
phrenia. Front Neurosci 8:1–5
Tsoi DT, Hunter MD, Woodruff PWR (2008) History, aetiology, and
symptomatology of schizophrenia. Psychiatry 7:404–409
U.S. Food and Drug Administration (2008a) Haldol® (haloperidol)
prescribing information. https://www.accessdata.fda.gov/drugsa
tfda_docs/label/2008/015923s082,018701s057lbl.pdf Accessed 6
March 2018
U.S. Food and Drug Administration (2013b) Seroquel® (quetiapine)
prescribing information. https://www.accessdata.fda.gov/drugsa
tfda_docs/label/2013/020639s061lbl.pdf Accessed 6 March 2018
U.S. Food and Drug Administration (2014c) Risperdal® (risperidone)
prescribing information. https://www.accessdata.fda.gov/drugsa
tfda_docs/label/2014/020272s073,020588s062,021444s048lbl.
pdf Accessed 6 March 2018
U.S. Food and Drug Administration (2014d) Abilify® (aripiprazole)
prescribing information. https://www.accessdata.fda.gov/drugsa
tfda_docs/label/2014/021436s038,021713s030,021729s022,
021866s023lbl.pdf Accessed 6 March 2018
Porsolt RD, Bertin A, Blavet N, et al. (1979) Immobility induced by
forced swimming in rats: effects of agents which modify central
catecholamine and serotonin activity. Eur J Pharmacol 57:201–10
Rzewuska M (2009) Układ dopaminergiczny i leki przeciwpsycho-
tyczne. Psychiatr w Prakt Klin 2:115–123
Schmidt AW, Lebel LA, Howard HR, Zorn SH (2001) Ziprasidone: a
novel antipsychotic agent with a unique human receptor binding
profile. Eur J Pharmacol 425:197–201
Słowiński T, Stefanowicz J, Dawidowski M et al. (2011) Synthesis
and biological investigation of potential atypical antipsychotics
with a tropane core. Part 1. Eur J Med Chem 46:4474–4488
Słowiński T, Stefanowicz J, Wróbel MZ et al. (2013) Model structure-
U.S. Food and Drug Administration (2015e) Clozaril® (clozapine)
prescribing information. https://www.accessdata.fda.gov/drugsa
tfda_docs/label/2015/019758s074lbl.pdf Accessed 6 March 2018
U.S. Food and Drug Administration (2015f) Zyprexa® (olanzapine)
prescribing information. https://www.accessdata.fda.gov/drugsa
tfda_docs/label/2015/020592s064,021086s042,021253s049lbl.
pdf Accessed 6 March 2018
U.S. Food and Drug Administration (2015g) Rexulti® (brexpiprazole)
prescribing information. https://www.accessdata.fda.gov/drugsa
tfda_docs/label/2015/205422s000lbl.pdf Accessed 6 March 2018
U.S. Food and Drug Administration (2015h) Vraylar[TM] (car-
iprazine) prescribing information. https://www.accessdata.fda.
activity relationship studies of potential tropane 5HT1A, 5HT2A
and D2 receptor ligands. Med Chem Res 22:3148–3153
,
gov/drugsatfda_docs/label/2015/204370lbl.pdf
March 2018
Accessed
6
Snyder SH (1976) The dopamine hypothesis of schizophrenia: focus
on the dopamine receptor. Am J Psychiatry 133:197–202
Stahl SM (2015) Mechanism of action of flibanserin, a multifunctional
serotonin agonist and antagonist (MSAA), in hypoactive sexual
desire disorder. CNS Spectr 20:1–6
Zajdel P, Marciniec K, Maślankiewicz A et al. (2012) Quinoline- and
isoquinoline-sulfonamide derivatives of LCAP as potent CNS
multi-receptor–5-HT1A/5-HT2A/5-HT7 and D2/D3/D4–agents: the
synthesis and pharmacological evaluation. Bioorg Med Chem
20:1545–1556
Stahl SM (2016) Mechanism of action of brexpiprazole: comparison
with aripiprazole. CNS Spectr 21:1–6