D2 Dopaminergic and 5-HT1A Serotonergic Activity of 2-(1-Naphthyl)ethyl- and 2-(2-Naphthyl)ethyl Amines

Article abstract of DOI:10.1002/ardp.200300776

Several tertiary 2-phenylethyl, 2-(1-naphthyl)ethyl and 2-(2-naphthyl) ethyl amines were synthesized and their binding affinities for dopamine D ₁, D₂ and serotonin 5-HT_1A receptors evaluated in radioligand binding assays.

Full text of DOI:10.1002/ardp.200300776

514 Šukalovic´ et al.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 514–522
V. Šukalovic´ a,
G. Rogli´ca,
D2 Dopaminergic and 5-HT1A Serotonergic Activity
of 2-(1-Naphthyl)ethyl- and 2-(2-Naphthyl)ethyl
Amines
S. Husineca,
S. Kostic´ -Raja´`ci´ca,
D. Andri´ca,
Vuki´c Šoški´ca,b,c
Several tertiary 2-phenylethyl, 2-(1-naphthyl)ethyl and 2-(2-naphthyl)ethyl amines
were synthesized and their binding affinities for dopamine D1, D2 and serotonin
5-HT1A receptors evaluated in radioligand binding assays.All compounds were inac-
tive in D1 dopamine radioligand binding assay. The 2-(1-naphthyl)ethyl analogues
expressed a low but significant binding affinity for the D2 and moderate one for the
5-HT1A receptor subtypes.Most of the remaining compounds expressed binding af-
finity at the 5-HT1A receptor subtype but were inactive in D2 receptor binding assay.
Based on these results and considering the chemical characteristics of the com-
pounds synthesized and evaluated for dopaminergic and serotonergic activity
throughout the present study it can be concluded that hydrophobic type of interac-
tion (stacking or edge-to-face) plays a significant role in the formation of receptor-lig-
and complexes of 2-(1-naphthyl)ethyl amines.This structural motive can be applied
to design and synthesize new, more potent dopaminergic/serotonergic ligands by
slight chemical modifications.
a
Centre for Chemistry,
Institute for Chemistry,
Technology and Metallurgy,
Belgrade, Yugoslavia
b
ProteoSys AG,
Mainz, Germany
Department of Medicine,
c
University College London,
London, UK
Keywords: 2-(1-Naphthyl)ethyl; 2-(2-Naphthyl)ethyl; Dopaminergic; Serotonergic;
D1; D2; 5-HT1A
Received: January 23, 2003; Accepted: April 28, 2003 [FP776]
DOI 10.1002/ardp.200300776
presence of two lipophilic sites which bind the N-alkyl
groups has been postulated [7].In our earlier studies we
Introduction
Recent application of molecular cloning technology re-
vealed a number of dopamine receptor (DAR) subtypes
belonging to the two main classes, D1-like (D1, D5) and
D2-like (D2, D3, D4) [1].These receptors have been asso-
ciated to the pathogenesis of neuropathological dis-
eases such as schizophrenia [2], Parkinson’s disease
[3], and ADHD (Attention Deficit Hyperactivity Disorder)
[4]. The therapeutic benefit of dopaminergic agents in
the treatment of psychotic disorders has been fully
recognized with the discovery of antipsychotic drugs ex-
pressing a high binding affinity at dopamine receptors.
have demonstrated that even the substituents as bulky
as 2-(1-naphthyl)ethyl can be accommodated in one of
these binding sites [8].
The model of McDermed et al.[6] has been employed as
a starting point in most dopamine D2 drug design strate-
gies [9].Using a similar approach we have designed and
explored the affinities of benzimidazole type ligands for
the binding at the D2 DAR [8].We have noticed that con-
sideration of only hydrogen and ionic bonds is not suffi-
cient to explain the affinities of these ligands for the bind-
ing at this class of DAR. It seems that the interaction of
hydrophobic type (e.g. stacking or edge-to-face interac-
tion) play a significant role in the formation of receptor-
ligand complexes and that for the better understanding
more attention should be paid to this type of interactions.
The binding sites of dopamine receptors occur in the
cavity formed among their seven, mostly hydrophobic,
membrane-spanning segments [5]. The surface of this
cavity contains residues that can interact with specific
agonists or antagonists and other residues that may af-
fect the steric conformation of the receptor itself, thus in-
directly affecting ligand binding.
To examine the contribution of hydrophobic interactions
in the formation of receptor-ligand complexes, we have
designed compounds (2 and 3) that share topological
similarities with benzimidazole pharmacophore (1), but
lack functional groups able to form strong hydrogen
bonds with the receptor molecule (Figure 1).This type of
interactions between compounds and the receptor
should be exclusively dependent on the shape of the lig-
and molecule and its ability to realize stacking or edge-
to-face interactions with aromatic residues in the binding
pocket of the receptor [10, 11].
McDermed et al. [6] suggested a model of DA pharma-
cophore by superpositioning of the pharmacophoric ele-
ments of DAR agonists, such as the nitrogen, nitrogen
lone pairs, oxygen and aromatic rings. In addition, the
Correspondence: Vukic´ Šoškic´, ProteoSys AG, Carl-Zeiss-
Str. 51, 55129 Mainz, Germany. Phone: +44 6131 50-192-46;
Fax: +44 6131 50-192-11; e-mail: vukic.soskic@proteosys.com
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2003, 336, 514–522
2-(1-naphthyl)ethyl- and 2-(2-naphthyl)ethyl amines 515
Figure 1. The structure of synthesized and evaluated tertiary 2-arylethyl amines.
Scheme 1. Synthesis of tertiary 2-arylethyl amines.
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

516 Šukalovic´ et al.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 514–522
Synthesis and binding properties of a series of such
compounds are discussed in the present study. In addi-
tion, new ligands have been evaluated for the binding af-
finity at the 5-HT1A receptor since some of benzimida-
zoles prepared and evaluated previously were shown to
be efficient displacers of the specific serotonin 5-HT1A
receptor radioligand [3H]-8-OH-DPAT.
Results and discussion
Binding affinity and selectivity of compounds
8a–l towards D1 and D2 dopamine and 5-HT1A
serotonin receptors
The final products 8a–l were evaluated for the binding
affinity at the D1 and D2 dopamine and serotonin 5-HT1A
receptors by in vitro competition displacement of the
specific radioligands from synaptosomal membranes
prepared from fresh bovine caudate nuclei (D1 and D2)
and hippocampi (5-HT1A). The Ki values for individual
compounds calculated from displacement curves are
listed in Table 1. Benzimidazole analogues 9–11 [12]
were run simultaneously in the same test systems as ref-
erences.
Chemistry
Chemical structure of the compounds synthesized
throughout the present work is depicted in Scheme 1.
Different arylacetic acids 4a–g were used as a starting
material to produce acylchlorides 5a–g using thionyl
chloride method.All tertiary amines (8a–l) were synthe-
sized by refluxing the appropriate amide (7a–l) with
B2H6 in THF for 60 min. The resulting crude products
were purified by silica gel column chromatography and
further converted to and crystallized as oxalic acid salts.
As seen from Table 1, none of the compounds synthe-
sized and evaluated for the dopaminergic/serotonergic
activity throughout the present study expressed the af-
finity for the binding at the D1 dopamine receptor. Com-
pounds 8f and 8l were completely inactive competitors
Table 1. Affinity and selectivity of the new ligands for the binding at the D1 and D2 dopamine and 5-HT1A serotonin re-
ceptors.
No
R2
R1
Ki S.E.M. (nM)
D2
D1
5-HT1A
8a
Phenyl
Phenyl
4-nitrophenyl
4-chlorophenyl
4-methylphenyl
1-naphthyl
2-naphthyl
1-naphthyl
2-naphthyl
1-naphthyl
1-naphthyl
Biphenyl
5-benzimidazole
5-benzimidazole
5-benzimidazole
H
>10 000
>10 000
>10 000
>10 000
>10 000
>10 000
>10 000
>10 000
>10 000
>10 000
>10 000
>10 000
>10 000
>10 000
>10 000
>10 000
>10 000
867 94
>10 000
>10 000
>10 000
>10 000
988 110
>10 000
2730 290
>10 000
>10 000
>10 000
1057 90
421 32
990 110
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
9
10
11
Phenyl
Phenyl
Phenyl
Phenyl
H
101
121 21
98
9
9
110 10
>10 000
532 73
H
Phenyl
Phenyl
1-naphthyl
2-naphthyl
phenyl
H
99
6
233 30
147 18
226 14
>10 000
465 64
126 11
160 24
phenyl
1-naphthyl
Values are the means of three independent experiments done in triplicate performed at eight competing ligand concen-
trations (10–4–10–9 M). [3H]SCH 23390 and [3H]Spiperone concentrations were 0.2 nM while [3H]-8-OH-DPAT was
0.6 nM per assay.
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2003, 336, 514–522
2-(1-naphthyl)ethyl- and 2-(2-naphthyl)ethyl amines 517
in both D2 and 5-HT1A binding assays. Besides, com-
pounds 8a, b, e, g, i, k, and 8l were poor competitors of
[3H]spiperone only.
group of the ligand 8l with Phe 178 of D2 dopamine re-
ceptor.Ligands with phenyl groups (8a, 8b, 8d and 8e)
were inactive in spiperone binding assay, with the only
exception of compound 8c. Since a phenyl group is
much less voluminous compared to a naphthyl group,
edge-to-face interactions are probably less likely to take
place. A significantly higher affinity of compound 8c for
the binding at the D2 dopamine receptor can be ex-
plained by possible hydrogen bond formation between
the nitro group of the ligand and hydrogen bond donor in
the D2 receptor binding pocket.
The remaining novel compounds acted as displacers of
[3H]spiperone and [3H]8-OH-DPAT expressing the bind-
ing affinity at the corresponding receptors in a micromo-
lar and nanomolar range of concentrations, respectively.
Among the naphthyl derivatives, compound 8h with a Ki
value of 988 nM and 99 nM was the most potent in dis-
placing [3H]spiperone and [3H]8-OH-DPAT from the D2
and 5-HT1A serotonin receptors, respectively.Most of the
tested compounds 8b–l expresseda similaraffinity with-
in the range of 100 nM for the binding at the 5-HT1A sero-
tonin receptor.The same compounds were more selec-
tive with regard to the binding at the D2 dopamine recep-
tor, 4-nitrophenylcompound8c with a Ki value of 867 nM
being the most active.
Binding constants of naphthyl compounds 8c and 8e
obtained in tritiated spiperone assay were similar to
those of thienylethylamines (compounds 3 and 4) de-
scribed by Dijkstra et al. [15]. These authors suggested
that the thiophene and the phenol ring utilize the same
interaction points and that the sulfur atom in the thienyl-
ethyl substituents forms a hydrogen bond with the hy-
droxyl moiety of a Ser residue in the D2 receptor. Al-
though this is a “pleasurable” explanation, additional (or
even exclusive) edge-to-face interactions of the thienyl
moiety of the ligands and aromatic residues in the bind-
ing pocket of the receptor molecule cannot be excluded.
With the exception of compound 8c, all synthesized
compounds were lacking groups able to build hydrogen
bonds attached to the aromatic rings.The only possible
stabilizing interaction of these compounds and the re-
ceptor can be that of hydrophobic type. According to the
generally accepted dopamine receptor model, there is a
cluster of aromatic amino acids in TM5 and TM6 of the
receptor that interact with the aromatic ring of ligands [5,
13, 14]. Recently, it has emerged that attractive interac-
tions of a different type exist between aromatic moieties
devoid of polar substituents.These “edge-to-face” inter-
actions, though modest in energy terms, can play an im-
portant role in such diverse areas as protein folding,
base pair stacking in DNA, host-guest binding in su-
pramolecular assemblies, crystal engineering, drug-re-
ceptor interactions and other molecular recognition
processes [10].This type of interactions can energetical-
ly stabilize the system up to –2.7 kcal/mol. Contribution
of hydrogen bond to complex stability is often exceeding
this value, what can be taken as the explanation for the
fact that the benzimidazole derivatives, which can form
hydrogen bonds, have higher affinities for the binding at
the D2 dopamine receptor, than the corresponding naph-
thyl derivatives.
It would be very interesting to introduce a naphthalene
structure in semirigid 2-aminotetralin-like structure in a
similar way as done with the thiophene ring and to evalu-
ate the binding affinity of thus obtained compounds. Re-
search in that direction is under way and we hope to pro-
duce the ligands of higher binding affinity than observed
for the compounds described in the present study. This
type of dopaminergic compounds would confirm our hy-
pothesis that edge-to-face interactions of ligands and
the receptor could be sufficient to create a high affinity
ligand.From a practical point of view, clinical utility of cat-
echol- and phenol-containing drugs has been limited
due to their low oral bioavailability and short duration of
action. Thus, for many years, emphasis has been fo-
cused on the identification of bioisosteric replacements
of both catechols and phenols.The idea that neither cat-
echolic nor phenolic hydroxyl groups are an absolute re-
quirement for potent dopaminergic activity is not new
[16] and we believe that our results contribute somewhat
to collective efforts to find more efficient dopaminergic
drugs.
Thus, we hypothesized that affinities of compounds 8h
and 8j for the binding at the D2 dopamine receptor are
due to edge-to-face interaction of 1-naphthyl group in
these ligands and aromatic amino acids in the receptor
bindingpocket.Hypotheticalmodelofedge-to-faceinter-
action between ligand 8h and D2 dopamine receptor is
presented in Figure 2.
The model of McDermed et al.[6] of the D2 dopamine re-
ceptor postulated the presence of two lipophilic sites
which bind the N-alkyl groups.One of these sites is large
enough to accommodate rather bulky groups. Introduc-
tion of different 2-arylethyl groups as substituents in this
position, lead to a significant increase in the affinity of
benzimidazole (1) [6] or phenylethylamine (R: m- or p-
OH) (3) [7] type of ligands in comparison with the paren-
tal ones.Similar pattern of behaviour has been observed
Inactivity of 2-naphthyl derivatives 8g and 8i, as well as
of biphenyl compound 8l can be interpreted in terms of
steric hindrance.According to the proposed model unfa-
vourable steric interactions occurs between 2-naphthyl
group of the compounds 8g and 8i as well as biphenyl
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

518 Šukalovic´ et al.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 514–522
Figure 2. Schematic representation of edge-to-face interaction between ligand 8h and D2 dopamine receptor.
Schematic model of the proposed interaction of the studied compound 8h with the D2 receptors.A:Cartoon describes
possible edge-to-face interaction between 8h and the aromatic residue in the binding pocket of the receptor. B: 3D
presentationof the sameinteractionusinga theoreticaldopamineD2 receptormodelonbacteriorhodopsin(PDBidenti-
fication code: 1I15, Protein Data Bank, Brookhaven) and ligand 8h.
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2003, 336, 514–522
2-(1-naphthyl)ethyl- and 2-(2-naphthyl)ethyl amines 519
in 0.4 % of the calculated values. 200 MHz 1H-NMR spectra re-
corded on a Gemini 2000 spectrometer (Varian, Palo Alto, CA,
USA) with CDCl3 as a solvent unless otherwise stated are re-
ported in ppm (δ) downfield from the internal standard tetrame-
thylsilane.The IR spectra were run on a Perkin Elmer 457 Grat-
ing Infrared Spectrophotometer (Perkin Elmer, Beaconsfield,
England). The mass spectra were determined on a Bruker Bi-
flex MALDI TOF mass spectrometer (Bruker, Bremen, Germa-
ny). For analytical thin-layer chromatography, E. Merck (Darm-
stadt, Germany) F-256 plastic-backed thin-layer silica gel
plates were used. Chromatographic purifications were per-
formed on Merck-60 silica gel columns, 230–400 mesh ASTM
under medium pressure (MPLC). Solutions were routinely
dried over anhydrous Na2SO4 prior to evaporation.
in 1-naphthyl derivatives 8f, 8h and 8j, while compound
8k was inactive due to the incompatibility of the 2-naph-
thyl group geometry with this receptor system.
The profile of activity detected in [3H]-8-OH-DPAT com-
petition binding assay revealed a rather high affinity but
relatively low structural selectivity of most of the ligands
discussed here. Lower structural selectivity for 5-HT1A
receptor compared to the D2 dopamine receptor can be
due to its more spacious and flexible ligand binding site.
This can be a pleasurable explanation for lower but are
still significant activities of 2-naphthyl ligands 8g and 8i.
Compounds 8f and 8l behaving as inactive competitors
of the specific radioligand were the only exception, while
compounds 8a and 8g had a rather low binding affinity.
As in the case of the D2 dopamine receptor, linking of the
2-arylethyl group to the basic nitrogen, significantly in-
creased the affinity of the ligands to bind at the 5-HT1A
receptor.The receptor binding pocket is large enough to
accommodate as bulky substituents as 2-(1-napthyl)-
ethyl and 2-(2-napthyl)ethyl, but not so voluminous sub-
stituent as 2-(biphenyl)ethyl [17].On the other hand, due
to chemical properties of the ligands examined in this
study, hydrophobic edge-to-face interactions represent
the principal driving force in ligand-receptor complex for-
mation.
Chemistry
General procedure for the synthesis of acyl chlorides (5 a–g)
Synthesis of acyl chlorides (5 a–g) was performed according to
the modified general procedure starting from the correspond-
ing acid and thionyl chloride [17]. Shortly, to the solution of
25 mmol arylacetic acids in 10 mL dichloromethane, 0.5 mL
DMF and 0.030 mol thionyl chloride were added. The mixture
was incubated at room temperature overnight.The solvent was
removed in vacuo and obtained acyl chlorides were used with-
out further purification for amides preparation.
General procedure for the synthesis of secondary amines
6 a–d
The details on the synthesis of secondary amines 6 a–d were
given previously [12].
General procedure for the synthesis of arylacetamides 7 a–l
In conclusion, these data demonstrate the affinity of ter-
tiary 2-(1-naphthyl)ethyl and 2-(2-naphthyl)ethyl amines
for the binding at the D2 dopamine and 5-HT1A serotonin
receptors.The lack of heteroatoms in the ligands which
could build strong hydrogen bonds with thereceptormol-
eculesclearly point to apronouncedroleofstabilizingar-
omatic stacking or edge-to-face interactions in the for-
mation of ligand-receptor complexes.
To the solution of each secondary amine 6 a–d (15 mmol) in
50 ml of dry dichloromethane and 15 mmol pyridine cooled in
an ice bath, 15 mmol solution of either acyl chloride (5 a–g) in
10 ml dichloromethane was added dropwise. After overnight
stirring at ambient temperature, the reaction mixture was ex-
tracted first with 5 % NaOH followed by 5 % HCl and water.After
drying over Na2SO4 organic phase was evaporated in vacuo to
dryness and the crude product purified by MPLC or crystallized
from ethanol.
Further elaboration of the chemical structure of the lig-
ands described in the present report, which focused on
the improvement of their dopaminergic/serotonergic
properties, and on providing a more precise map of the
receptor site interacting with naphthyl derivatives is in
progress.
N,N-dipropyl-2-phenylacetamide (7 a):
Yield 3.00 g (92 %); oil – IR (KBr): (cm–1) 2962, 1641, 1089,
793.– 1H-NMR:δ 0.92 (t, J = 8 Hz, 6 H, CH2CH2CH3);1.45 (tq, J
= 8 Hz, 4 H, CH2CH2CH3); 3.1–3.2 (m, 4 H, CH2CH2CH3); 3.62
(s, 2 H, PhCH2CON); 7.21 (s broad, 5 H, PhH). – Anal.
(C14H21NO), C,H,N.[18]
N-propyl-N-(2-phenylethyl)-2-phenylacetamide (7 b):
Yield 3.75 g (89 %); mp 62 °C. – IR (KBr): (cm–1) 2960, 1659,
Acknowledgement
1
1061, 792. – H-NMR: δ 0.93 (t, J = 8 Hz, 3 H, CH2CH2CH3);
This work was supported by the Ministry for Science,
Technology and Development of Serbia, Project No.
1698 (V. Šukalovi´c, G.R., S.H., S.K.-R. and D.D.) and
ProteoSys AG (V. Šoškic´).
1.40–1.70 (m, 4 H, CH2CH2CH3); 2.70 (t, J = 8 Hz, 2 H,
CH2CH2CH3); 3.0–3.25 (m, 4 H, PhCH2CH2N, CH2CH2CH3);
3.46–3.60 (m, 2 H, PhCH2CH2N); 3.64 (s, 2 H, PhCH2CON);
7.22 (m, 10 H, PhH). – Anal. (C19H23NO), C,H,N.
N-propyl-N-(2-phenylethyl)-2-(4-nitrophenyl)acetamide (7 c):
Yield 3.86 g (79 %); mp 115 °C. – IR (KBr): (cm–1) 2939, 1654,
1553, 1490, 1065, 781. – H-NMR: δ 0.91 (t, J = 8 Hz, 3 H,
Experimental
1
CH2CH2CH3); 1.40–1.70 (m, 4 H, CH2CH2CH3); 2.70 (t, J =
8 Hz, 2 H, CH2CH2CH3); 3.0–3.35 (m, 4 H, PhCH2CH2N,
CH2CH2CH3); 3.55–3.69 (m, 2 H, PhCH2CH2N); 3.91 (s, 2 H,
PhCH2CON); 7.24 (s broad, 5 H, PhH); 7.63 (d, J = 8 Hz, 2 H,
ArH); 8.22 (d, J = 8 Hz, 2 H, ArH). – Anal. (C19H22N2O3), C,H,N.
General
Melting points of the novel ligands determined on a Boetius
PHMK apparatus (VEB Analytic, Dresden, Germany) are pre-
sented as uncorrected.The results of microanalyses were with-
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

520 Šukalovic´ et al.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 514–522
N-propyl-N-(2-phenylethyl)-2-(4-biphenyl)acetamide (7l):
N-propyl-N-(2-phenylethyl)-2-(4-chlorophenyl)acetamide (7d):
Yield 3.48 g (87 %); mp 103 °C. – IR (KBr): (cm–1) 2987, 1652,
Yield 4.25 g (90 %); mp 95 °C. – IR (KBr): (cm–1) 2961, 1659,
798.– 1H-NMR:δ 0.90 (t, J = 8 Hz, 3 H, CH2CH2CH3);1.40–1.70
(m, 4 H, CH2CH2CH3);2.70 (t, J = 8 Hz, 2 H, CH2CH2CH3);3.0–
3.25 (m, 4 H, PhCH2CH2N, CH2CH2CH3); 3.46–3.60 (m, 2 H,
PhCH2CH2N); 3.69 (s, 2 H, PhCH2CON); 7.20–7.40 (m, 9 H,
ArH). – Anal. (C19H22ClNO), C,H,N.
1
1073, 777. – H-NMR: δ 0.90 (t, J = 8 Hz, 3 H, CH2CH2CH3);
1.40–1.70 (m, 4 H, CH2CH2CH3); 2.70 (t, J = 8 Hz, 2 H,
CH2CH2CH3); 3.0–3.25 (m, 4 H, PhCH2CH2N, CH2CH2CH3);
3.46–3.60 (m, 2 H, PhCH2CH2N); 3.67 (s, 2 H, PhCH2CON);
7.1–7.8 (m, 14 H, ArH). – Anal. (C25H27NO), C,H,N.
General procedure for the synthesis of tertiary amines (8 a–l)
N-propyl-N-(2-phenylethyl)-2-(4-methylphenyl)acetamide (7e):
Yield 3.93 g (89 %); mp 61 °C. – IR (KBr): (cm–1) 2963, 1649,
1068, 792. – H-NMR: δ 0.93 (t, J = 8 Hz, 3 H, CH2CH2CH3);
A solution of each arylacetamide 7 a–l (10 mmol) in 30 ml of dry
tetrahydrofurane cooled in an ice bath was bubbled with gase-
ous diborane generated from 1.1 g NaBH4 and 5.0 mL
BF3 · Et2O. After diborane generation was ceased, the mixture
was refluxed for 60 min, cooled to ambient temperature, made
alkaline with 20 % NaOH, and extracted with diethyl ether.The
extract was evaporated in vacuo to dryness, the crude product
purified by MPLC and converted to oxalate by neutralization of
the amine with oxalic acid solution in 90 % ethanol.The result-
ing oxalates were subjected to recrystallization from ethanol.
1
1.40–1.70 (m, 4 H, CH2CH2CH3); 2.33 (s, 3 H, Ar-CH3); 2.70 (t,
J = 8 Hz, 2 H, CH2CH2CH3); 3.0–3.25 (m, 4 H, PhCH2CH2N,
CH2CH2CH3); 3.46–3.60 (m, 2 H, PhCH2CH2N); 3.64 (s, 2 H,
PhCH2CON); 7.20–7.40 (m, 9 H, ArH). – Anal. (C20H25NO),
C,H,N.
N,N-dipropyl-2-(1-naphthyl)acetamide (7 f):
Yield 3.02 g (75 %); mp 71 °C. – IR (KBr): (cm–1) 2959, 1663,
1
1061, 800. – H-NMR: δ 0.92 (t, J = 8 Hz, 6 H, CH2CH2CH3);
N-(2-phenylethyl)-N,N-dipropyl amine (8 a):
1.48 (tq, J = 8 Hz, 4 H, CH2CH2CH3); 3.2–3.3 (m, 4 H,
CH2CH2CH3);4.16 (s, 2 H, PhCH2CON);7.2–7.9 (m broad, 7 H,
ArH). – Anal. (C18H23NO), C,H,N.
Yield 1.86 g (91 %); mp 132 °C (oxalate). – IR (KBr): (cm–1)
2962, 1643, 1089. – 1H-NMR: δ 0.90 (t, J = 8 Hz, 6 H,
CH2CH2CH3); 1.70–1.40 (m, 4 H, CH2CH2CH3); 2.70 (t, J = 8
Hz, 4 H, CH2CH2CH3);2.90 (s broad, 4 H, PhCH2CH2N);7.21 (s
broad, 5 H, PhH); mass spectrum m/e 205,185 (M+). – Anal.
(C14H23N · C2H2O4 · H2O), C,H,N. [18]
N,N-dipropyl-2-(2-naphthyl)acetamide (7 g):
Yield 3.40 g (89 %); mp 82 °C. – IR (KBr): (cm–1) 2983, 1659,
1
1059, 789. – H-NMR: δ 0.92 (t, J = 8 Hz, 6 H, CH2CH2CH3);
1.43 (tq, J = 8 Hz, 4 H, CH2CH2CH3); 3.1–3.2 (m, 4 H,
CH2CH2CH3);3.98 (s, 2 H, PhCH2CON);7.2–7.9 (m broad, 7 H,
ArH). – Anal. (C18H23NO), C,H,N.
N,N-di(2-phenylethyl)-N-propyl amine (8 b):
Yield 2.35 g (88 %); mp 147 °C (oxalate). – IR (KBr): (cm–1)
2962, 1641, 1061. – 1H-NMR: δ 0.90 (t, J = 8 Hz, 3 H,
CH2CH2CH3); 1.70–1.40 (m, 2 H, CH2CH2CH3); 2.70 (t, J =
8 Hz, 2 H, CH2CH2CH3);2.91 (s broad, 8 H, PhCH2CH2N);7.22
(s broad, 10 H, PhH);mass spectrum m/e 267,202 (M+).– Anal.
(C19H25N · C2H2O4 · H2O), C,H,N. [19]
N-propyl-N-(2-phenylethyl)-2-(1-naphthyl)acetamide (7 h):
Yield 3.72 g (75 %); mp 125 °C. – IR (KBr): (cm–1) 2988, 1648,
1
1119, 801. – H-NMR: δ 0.92 (t, J = 8 Hz, 3 H, CH2CH2CH3);
1.45 (tq, J = 8 Hz, 2 H, CH2CH2CH3); 3.05 (s broad, 2 H,
PhCH2CH2N); 3.05–3.6 (m broad, 4 H, ArCH2CH2N); 4.15 (s,
2 H, PhCH2CON); 7.1–7.8 (m broad, 12 H, ArH). – Anal.
(C23H25NO), C,H,N.
N-(2-phenylethyl)-N-[2-(4-nitrophenyl)ethyl]-N-propyl amine
(8 c):
Yield 2.25 g (72 %); mp 174 °C (oxalate). – IR (KBr): (cm–1)
2956, 1633, 1555, 1497, 1065. – 1H-NMR: δ 0.90 (t, J = 8 Hz,
3 H, CH2CH2CH3);1.70–1.40 (m, 2 H, CH2CH2CH3);2.70 (t, J =
8 Hz, 2 H, CH2CH2CH3);2.92 (s broad, 2 H, PhCH2CH2N);3.05
(s broad, 6 H, ArCH2CH2N); 7.24 (s broad, 5 H, PhH); 7.63 (d,
J = 8 Hz, 2 H, ArH);8.22 (d, J = 8 Hz, 2 H, ArH);mass spectrum
m/e 312,187 (M+). – Anal. (C19H24N2O2 · C2H2O4 · H2O), C,H,N.
N-propyl-N-(2-phenylethyl)-2-(2-naphthyl)acetamide (7 i):
Yield 4.12 g (83 %); mp 129 °C. – IR (KBr): (cm–1) 2966, 1663,
1
1065, 791. – H-NMR: δ 0.91 (t, J = 8 Hz, 3 H, CH2CH2CH3);
1.43 (tq, J = 8 Hz, 2 H, CH2CH2CH3); 2.90 (s broad, 2 H,
PhCH2CH2N); 2.95–3.5 (m broad, 4 H, ArCH2CH2N); 3.92 (s,
2 H, PhCH2CON); 7.1–7.8 (m broad, 12 H, ArH). – Anal.
(C23H25NO), C,H,N.
N-(2-phenylethyl)-N-[2-(4-chlorophenyl)ethyl]-N-propyl amine
(8 d):
N-propyl-N-[2-(1-naphthyl)ethyl]-2-(1-naphthyl)acetamide (7j):
Yield 2.55 g (85 %); mp 158 °C (oxalate). – IR (KBr): (cm–1)
Yield 3.94 g (69 %); mp 135 °C. – IR (KBr): (cm–1) 2995, 1633,
1
2957, 1639, 1075, 795. – H-NMR: δ 0.90 (t, J = 8 Hz, 3 H,
1
1044, 781. – H-NMR: δ 0.94 (t, J = 8 Hz, 3 H, CH2CH2CH3);
CH2CH2CH3); 1.70–1.40 (m, 2 H, CH2CH2CH3); 2.70 (t, J =
8 Hz, 2 H, CH2CH2CH3); 2.92 (s broad, 8 H, ArCH2CH2N); 7.24
(s broad, 9 H, ArH); mass spectrum m/e 301,163 (M+). – Anal.
(C19H24ClN · C2H2O4 · H2O), C,H,N.
1.49 (tq, J = 8 Hz, 2 H, CH2CH2CH3); 3.2–3.3 (m, 2 H,
CH2CH2CH3); 3.35–3.8 (m, 4 H, ArCH2CH2N); 4.16 (s, 2 H,
PhCH2CON); 7.2–7.9 (m broad, 14 H, ArH).
– Anal.
(C27H27NO), C,H,N.
N-(2-phenylethyl)-N-[2-(4-methylphenyl)ethyl]-N-propyl amine
(8 e):
N-propyl-N-[2-(1-naphthyl)ethyl]-2-(2-naphthyl)acetamide (7k):
Yield 4.41 g (77 %); mp 141 °C. – IR (KBr): (cm–1) 2991, 1643,
Yield 2.61 g (93 %); mp 149 °C (oxalate). – IR (KBr): (cm–1)
2976, 1653, 1077. – 1H-NMR: δ 0.90 (t, J = 8 Hz, 3 H,
CH2CH2CH3);1.70–1.40 (m, 2 H, CH2CH2CH3);2.33 (s, 3 H, Ar-
CH3); 2.70 (t, J = 8 Hz, 2 H, CH2CH2CH3); 2.90 (s broad, 8 H,
ArCH2CH2N); 7.18 (s broad, 9 H, ArH); mass spectrum m/e
281,216 (M+). – Anal. (C20H27N · C2H2O4 · H2O), C,H,N.
1
1088, 788. – H-NMR: δ 0.90 (t, J = 8 Hz, 3 H, CH2CH2CH3);
1.70–1.40 (m, 3 H, CH2CH2CH3); 2.70 (t, J = 8 Hz, 2 H,
CH2CH2CH3);2.96 (m broad, 6 H, ArCH2CH2N);3.21 (m broad,
2 H, 1-naphthyl-CH2CH2N); 7.2–7.9 (m broad, 14 H, ArH). –
Anal. (C27H27NO), C,H,N.
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2003, 336, 514–522
2-(1-naphthyl)ethyl- and 2-(2-naphthyl)ethyl amines 521
Radioligand binding studies
N-[2-(1-naphthyl)ethyl]-N,N-dipropyl amine (8 f):
Yield 2.26 g (89 %); mp 143 °C (oxalate). – IR (KBr): (cm–1)
2956, 1633, 1065. – 1H-NMR: δ 0.90 (t, J = 8 Hz, 6 H,
CH2CH2CH3); 1.70–1.40 (m, 4 H, CH2CH2CH3); 2.70 (t, J =
8 Hz, 4 H, CH2CH2CH3);2.96 (m broad, 2 H, ArCH2CH2N);3.21
(m broad, 2 H, 1-naphthyl-CH2CH2N); 7.2–7.9 (m broad, 7 H,
ArH); mass spectrum m/e 255,195 (M+). – Anal. (C18H25N ·
C2H2O4 · H2O), C,H,N.
Synaptosomal membranes of fresh bovine caudate nuclei and
hippocampi used in radioligand binding assays as sources of
the dopamine and serotonin receptors, respectively, were pre-
pared as described previously [20, 21]. [3H]SCH 23390 (spec.
act. 80 Ci mmol–1), [3H]spiperone (spec act. 70.5 Ci mmol–1)
and [3H]-8-OH-DPAT (spec act.223 Ci mmol–1) used to label D1,
D2 and 5-HT1A receptors, respectively, were purchased from
Amersham Buchler GmbH (Braunschweig, Germany).Compe-
tition binding assays in which the novel ligands served as com-
petitors and data analyses were performed exactly as reported
previously [19].
N-[2-(2-naphthyl)ethyl]-N,N-dipropyl amine (8 g):
Yield 2.11 g (86 %); mp 148 °C (oxalate). – IR (KBr): (cm–1)
2993, 1654, 1059. – 1H-NMR: δ 0.90 (t, J = 8 Hz, 6 H,
CH2CH2CH3); 1.70–1.40 (m, 4 H, CH2CH2CH3); 2.70 (t, J =
8 Hz, 4 H, CH2CH2CH3); 2.95 (s broad, 4 H, 2-naphthyl-
CH2CH2N); 7.2–7.9 (m broad, 7 H, ArH); mass spectrum m/e
255,195 (M+). – Anal. (C18H25N · C2H2O4 · H2O), C,H,N.
Receptor-binding assay using [3H]Spiperone
[3H]Spiperone binding was assayed at membrane protein con-
centration of 0.7 mg/mL in a solution consisting of (in mM):
EDTA 1.0, MgCl2 4.0, CaCl2 1.5, KCl 5.0, NaCl 120,Tris-HCl 25,
pH 7.4, at 37 °C for 20 min in a total volume of incubation mix-
ture of 1.0 mL. Binding of the radioligand to 5-HT2 receptors
was prevented by 50 nM ketanserin. IC50 values were deter-
mined by competition binding at 0.2 nM of the radioligand and
eight to ten concentrations of each novel compound (0.1 nM –
0.1 mM).Nonspecific binding was measured in the presence of
1.0 µM (+)-butaclamol.The reaction was terminated by a rapid
filtration through Whatman GF/C filters, which were further
washed three times with 5.0 mL of ice-cold incubation buffer.
Each point was determined in triplicate. Retained radioactivity
was measured by introducting dry filters into 10 ml of toluene-
based scintillation liquid and counting in a 1219 Rackbeta Wal-
lac scintillation counter at an efficiency of 51-55 % for tritium.
N-[2-(1-naphthyl)ethyl]-N-(2-phenylethyl)-N-propyl
amine
(8 h):
Yield 2.50 g (79 %); mp 163 °C (oxalate). – IR (KBr): (cm–1)
2978, 1658, 1101. – 1H-NMR: δ 0.90 (t, J = 8 Hz, 3 H,
CH2CH2CH3); 1.70–1.40 (m, 3 H, CH2CH2CH3); 2.70 (t, J = 8
Hz, 2 H, CH2CH2CH3); 2.94 (m broad, 6 H, PhCH2CH2N, 1-
naphthyl-CH2CH2N ); 3.21 (m broad, 2 H, 1-naphthyl-
CH2CH2N); 7.2–7.9 (m broad, 12 H, ArH); mass spectrum m/e
317,214 (M+). – Anal. (C23H27N · C2H2O4 · H2O), C,H,N.
N-[2-(2-naphthyl)ethyl]-N-(2-phenylethyl)-N-propylamine(8 i):
Yield 2.54 g (80 %); mp 168 °C (oxalate). – IR (KBr): (cm–1)
2973, 1651, 1071. – 1H-NMR: δ 0.90 (t, J = 8 Hz, 3 H,
CH2CH2CH3); 1.70–1.40 (m, 2 H, CH2CH2CH3); 2.70 (t, J =
8 Hz, 2 H, CH2CH2CH3); 2.90 (s broad, 4 H, PhCH2CH2N, 2-
naphthyl-CH2CH2N);2.95 (m broad, 4 H, PhCH2CH2N, 2-naph-
thyl-CH2CH2N); 7.1–7.8 (m broad, 14 H, ArH); mass spectrum
m/e 317,217 (M+). – Anal. (C23H27N · C2H2O4 · H2O), C,H,N.
Receptor- binding assay using [3H]SCH 23390
Binding of [3H]SCH 23390 was examined by the same rapid fil-
tration assay discussed for [3H]spiperone in the absence of ket-
anserin.
Receptor-binding assay using [3H]-8-OH-DPAT
To achieve a final volume of 0.5 mL, a solution containing (in
mM) EDTA 1.0, MgCl2 4.0, CaCl2 1.5, KCl 5.0, NaCl 120, Tris-
HCl 25, pH 7.4, 10 µM nialamide and 0.1 % ascorbic acid, at
membrane protein concentration of 0.7 mg/ml, 0.6 nM [3H]-8-
OH-DPAT and various concentrations (0.1 nM – 0.1 mM) of the
tested compounds were introduced into each tube.The incuba-
tion, termination of the reaction and handling of the filters were
done as described in the [3H]spiperone binding assay. Specific
binding at the 5-HT1A receptor was defined as the difference
between the binding in the absence and in the presence of
10 µM 5-hydroxytryptamine.
N,N-di[2-(1-naphthyl)ethyl]-N-propyl amine (8 j):
Yield 2.38 g (65 %); mp 148 °C (oxalate). – IR (KBr): (cm–1)
2990, 1649, 1047. – 1H-NMR: δ 0.90 (t, J = 8 Hz, 3 H,
CH2CH2CH3); 1.70–1.40 (m, 2 H, CH2CH2CH3); 2.70 (t, J =
8 Hz, 4 H, CH2CH2CH3);2.96 (m broad, 4 H, ArCH2CH2N);3.21
(m broad, 4 H, 1-naphthyl-CH2CH2N); 7.2–7.9 (m broad, 14 H,
ArH); mass spectrum m/e 367,236 (M+). – Anal. (C27H29N ·
C2H2O4 · H2O), C,H,N.
N-[2-(1-naphthyl)ethyl]-N-[2-(2-naphthyl)ethyl]-N-propyl amine
(8k):
Yield 2.60 g (71 %); mp 154 °C (oxalate). – IR (KBr): (cm–1)
2983, 1637, 1085. – 1H-NMR: δ 0.90 (t, J = 8 Hz, 3 H,
CH2CH2CH3); 1.70–1.40 (m, 2 H, CH2CH2CH3); 2.70 (t, J =
8 Hz, 2 H, CH2CH2CH3); 2.96 (m broad, 6 H, PhCH2CH2N, 2-
naphthyl-CH2CH2N); 3.21 (m broad, 2 H, 1-naphthyl-
CH2CH2N); 7.2–7.9 (m broad, 14 H, ArH); mass spectrum m/e
367,231 (M+). – Anal. (C27H29N · C2H2O4 · H2O), C,H,N.
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Key-Technologies of the Future
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