Synthesis and binding affinity of novel 3-aminoethyl-1-tetralones, potential atypical antipsychotics

Article abstract of DOI:10.1016/j.bmcl.2005.04.022

A series of 3-aminoethyl-1-tetralones, conformationally constrained higher homologues of haloperidol (standard for typical antipsychotic profile), have been obtained by a four-step route from valerolactone. Their binding affinities at dopamine D₂ and serotonin 5-HT_2A and 5-HT_2C receptors were determined, showing in some cases an atypical antipsychotic profile.

Full text of DOI:10.1016/j.bmcl.2005.04.022

Bioorganic & Medicinal Chemistry Letters 15 (2005) 3063–3066
Synthesis and binding affinity of novel
3-aminoethyl-1-tetralones, potential atypical antipsychoticsq
b
Mario Alvarado,a Alberto Coelho,a Christian F. Masaguer,a Enrique Ravin˜a,a, Jose Brea,
*
´
b
J. Fernando Padın and Marıa I. Loza
b
´
´
a
´
´
´
´
Departamento de Quımica Organica, Laboratorio de Quımica Farmaceutica, Facultad de Farmacia,
Universidad de Santiago de Compostela. E-15782, Santiago de Compostela, Spain
b
´
Departamento de Farmacologıa, Facultad de Farmacia, Universidad de Santiago de Compostela. E-15782,
Santiago de Compostela, Spain
Received 4 February 2005; revised 1 April 2005; accepted 14 April 2005
Available online 5 May 2005
Abstract—A series of 3-aminoethyl-1-tetralones, conformationally constrained higher homologues of haloperidol (standard for typ-
ical antipsychotic profile), have been obtained by a four-step route from valerolactone. Their binding affinities at dopamine D2 and
serotonin 5-HT2A and 5-HT2C receptors were determined, showing in some cases an atypical antipsychotic profile.
Ó 2005 Elsevier Ltd. All rights reserved.
Schizophrenia is a disease of unknown aetiology affect-
ing approximately 1% of the population. Classical (typ-
ical) neuroleptics such as haloperidol (Fig. 1) are
currently used for the treatment of this disease, but their
use is associated with severe mechanism-related side
effects, including induction of acute extrapyramidal
symptoms (EPS).1 The clinical efficacy of classical
antipsychotics in the treatment of schizophrenia and
other psychotic disorders is directly related to their abil-
ity to block dopamine D2 receptors in the brain;2 how-
ever, it has been reported that dopamine receptor
blockade in the striatum is closely associated with their
extrapyramidal side effects.3
The introduction of clozapine for treatment-resistant
schizophrenia gave rise to a new group of atypical or
non-classical antipsychotics, which have no EPS and
are effective against negative symptoms.4 These drugs ex-
hibit potent antagonism at multiple receptor subtypes
including dopamine and specially serotonin receptors,
hinting at the implication of the serotoninergic system
in this pathology.5 Meltzer et al.6 suggested that in the
efficacy of clozapine and other atypical antipsychotics
the most important factor is their relative affinities for
D2 and 5-HT2A receptors.7 They proposed that the ratio
between pKi for 5-HT2A and pKi for D2 may be used to
discriminate atypical antipsychotics (ratio >1.12) from
classical antipsychotics (ratio <1.09). Experimental and
clinical studies seem to confirm the major role of the 5-
HT2A receptor for the atypical profile of the antipsycho-
tics;8 on the other hand, many of these drugs block not
only 5-HT2A but other serotonin receptors, particularly
5-HT2C receptors,9 and this blockade has been suggested
to be responsible for reducing EPS.10 These findings have
given cause for 5-HT2C receptor to be also considered as
a potential target in the treatment of psychotic ill-
nesses.11 Clozapine remains the prototype of atypical
Figure 1. Prototypes of typical (haloperidol) and atypical (clozapine)
antipsychotics.
Keywords: Aminoethyltetralones; Valerophenones; Dopamine recep-
tors; Serotonin receptors; Antipsychotics.
q This is the 32nd paper in the series ꢀSynthesis and CNS Activity of
Conformationally Restricted Butyrophenonesꢁ; for preceding paper,
see Ref. 14.
*
Corresponding author. Tel.: +34 981 594 628; fax: +34 981 594
912; e-mail: qofara@usc.es
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.04.022

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M. Alvarado et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3063–3066
Figure 2.
antipsychotic drugs and no currently available agents ap-
pear to have the spectrum of efficacy of this drug. How-
ever, treatment with clozapine is associated with an
increased risk of agranulocytosis,12 which strongly limits
its therapeutic use. Hence, the discovery of a more effec-
tive side effects free therapy for the treatment of schizo-
phrenia remains a challenging research goal.
lones II (conformationally restricted aminobutyrophe-
nones). Although the butyrophenone moiety has been
accepted as an optimized side chain for the D2 receptor,1
remarkable increases in affinity at this receptor have
been described with the elongation of the chain length
of the butyrophenone to the valerophenone moiety.15
Also, extension of butyrophenones to valerophenones
has been reported to enhance r-receptor affinity,16 and
these receptors have been pointed out as potential sites
of action of atypical antipsychotics.17
We have reported the synthesis, pharmacological activ-
ity and molecular modelling of the aminoalkylbenzocy-
cloalkanones I (Fig. 2), which are conformationally
restricted butyrophenone analogues of haloperidol,13
as part of a program aimed at developing potential atyp-
ical antipsychotic compounds. Between these com-
pounds, the favourable pharmacological profile of the
tetralone derivatives II14 has prompted us to explore
the structure–activity relationships of this system as a
scaffold for the design of new analogues of haloperidol.
Herein, we wish to report the synthesis of 3-aminoethyl-
1-tetralones (IIIa) and 3-aminoethyl-7-methoxy-1-tetra-
lones (IIIb), and their binding affinities on D2, 5-HT2A
and 5-HT2C receptors. These compounds correspond
to a series of CNS agents (aminovalerophenones), which
are higher homologues of the 3-aminomethyl-1-tetra-
In the first stage of this research, we want to explore, as
part of the general structure III, different amine moieties
(Table 1) present in several CNS agents: arylpiperazines
such as N-(2-methoxyphenyl)-piperazine and N-(2-pyr-
idyl)piperazine (present in fluanisone and buspirone,
respectively), a substituted piperidine (N-(6-fluoro-
benzisoxazol-3-yl)piperidine, the amine of the antipsy-
chotic risperidone), and two 1,3,8-triazaspirodecanones
related to spiperone.
The target 3-aminoethyltetralones IIIa-b were prepared
as shown in Scheme 1. Benzyl-lactones 1a,b were synthe-
sized by TMSCl-TMEDA activated cuprate addition18
Table 1. Binding affinities for aminoethyltetralones 4a,b–8a,b (see Scheme 1) and reference antipsychoticsa
Compound
R
NR0R0
pKib
pKi ratio
5-HT2A/D2
5-HT2A
5-HT2C
D2
4a
4b
H
OCH3
6.59 0.29
6.65 0.07
6.35 0.10
5.72 0.21
6.97 0.19
6.55 0.34
0.95
1.01
5a
5b
H
OCH3
6.54 0.11
6.33 0.11
<5
5.81 0.20
<5
<5
—
—
6a
6b
H
OCH3
8.29 0.25
8.23 0.14
7.06 0.11
6.89 0.19
5.98 0.42
7.04 0.31
1.38
1.17
7a
7b
H
OCH3
<5
<5
<5
<5
<5
<5
—
—
8a
8b
H
OCH3
6.15 0.13
5.98 0.15
7.05 0.18
6.90 0.21
<5
<5
—
—
Haloperidol
Clozapine
6.78 0.25
8.04 0.31
5.14 0.18
7.98 0.11
9.22 0.12
6.65 0.17
0.73
1.21
a For binding assay methods, see Ref. 13.
b Values are means of three separate experiments (s.e.m. less than 6%).

M. Alvarado et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3063–3066
3065
Table 2. Binding affinities for aminovalerophenones 6a,b and amino-
butyrophenones 15–17
Compd
n
R6
R7
H
pKia
pKi ratio
5-HT2A/D2
5-HT2A 5-HT2C D2
6a
2
2
1
1
1
H
8.29
7.06
6.89
6.89
5.79
6.83
5.98 1.38
6b
H
OCH3 8.23
7.04 1.17
7.24 1.18
6.34 1.16
6.82 1.18
15b
16b
17b
H
OCH3
H
H
8.57
7.34
OCH3 OCH3 8.02
a Values are means of three separate experiments (s.e.m. less than 6%).
b Data from Ref. 14.
The 1,3,8-triazaspirodecanone derivatives 7a and 7b
lack affinity at the three targeted receptors. On the con-
trary, compounds bearing a 1,3,8-triazaspirodecandione
moiety (i.e., 8a and 8b) behave as 5-HT2 selective li-
gands: display significant affinity for the 5-HT2 receptors
assayed, with about 10-fold higher affinity for 5-HT2C
receptors, and also lack affinity at D2 receptors. The ex-
tra carbonyl group in 8a,b versus 7a,b seems to enhance
affinity at 5-HT2C receptors and, to a small extent, at 5-
HT2A receptors, which is in accordance with the binding
profile of some reported 1,3,8-triazaspirodecane
derivatives.20
Scheme 1. Reagents: (i) CuI, TMEDA, TMSCl, THF (60–70%); (ii)
HBr/AcOH 33% (88–95%); (iii) TFA, TFAA (75%); (iv) HNR0R0,
Na2CO3, KI, MIK (50–90%); (v) CH2N2, Et2O (98%); (vi) HNR0R0,
Na2CO3, KI, MIK (30–75%); (vii) PPA (20–50%).
of benzyl (or 4-methoxybenzyl) to 5,6-dihydro-2H-pyr-
an-2-one in 60–70% yield. Reaction of lactones 1a,b with
hydrogen bromide in acetic acid afforded the stable 5-
bromo-3-benzylvaleric acids 2a,b, which were cyclized
with trifluoroacetic acid-trifluoroacetic anhydride to
give the corresponding 3-bromoethyltetralones 3a,b in
75–78% yield. Subsequent nucleophilic substitution of
bromine with secondary amines (see Table 1) in basic
methyl isobutyl ketone led to the 3-aminoethyltetralones
4a,b–8a,b in good to excellent yields.
On the basis of the 5-HT2A/D2 antagonism hypothesis, it
is worth mentioning compounds 6a and 6b as potential
atypical antipsychotics,21 with a Meltzerꢁs ratio of 1.38
and 1.17, respectively, both higher than 1.12, the value
from which Meltzer predicts an atypical profile for anti-
psychotics.6 Both compounds exhibit similar affinities at
5-HT2A and 5-HT2C receptors, while at the D2 receptor
compound 6b displays 10-fold higher affinity than 6a,
hinting at a favourable effect of the 7-methoxy substitu-
ent on the D2 receptor binding.
Alternatively, bromoacid 2a was esterified with di-
azomethane to quantitatively afford the bromoester 9a,
which, by nucleophilic substitution with amines in the
presence of Na2CO3 and catalytic IK, led to the b-ben-
zyl-x-aminoesters 10a–14a in 30–75% yield. Finally,
acid-catalyzed ring closure with polyphosphoric acid
gave the final aminoethyltetralones in 20–50% yield.
In comparison with their butyrophenone analogues,14
benzisoxazolylpiperidine compounds 6a and 6b (Table
2) exhibit similar affinities and selectivities for the
5-HT2A, 5-HT2C and D2 receptors, with a pKi ratio 5-
HT2A/D2 higher than 1.15 in all five compounds. In con-
clusion, enlargement of the methylene bridge between
piperidine and the tetralone ring by one CH2 did not
cause decrease of affinity at the three receptors tested.
The binding affinities of the aminoethyltetralones 4a,b–
8a,b at the 5-HT2A, 5-HT2C and dopamine D2 recep-
tors are summarized in Table 1. Aminoethyltetralones
containing a 4-(o-methoxyphenyl)piperazine fragment
(compounds 4a and 4b) show modest and similar affinity
at the three receptors tested, while those compounds
bearing a 4-(2-pyridyl)piperazine, that is 5a and 5b, lack
appreciable affinity for dopamine D2 receptors. Because
of this low affinity at D2 receptors, compounds 5a and
5b do not possess interest as potential antipsychotics,
but 5a could have an interesting profile as selective 5-
HT2A compound. However, some of these piperazine
compounds could bind at r receptors because they pos-
sess structural characteristics that are favourable for
such binding.19
In summary, we have described the synthesis and bind-
ing affinity of new 3-aminoethyltetralones as conforma-
tionally constrained higher homologues of haloperidol.
From this work has emerged the benzisoxazolylpiperi-
dine compound 6b, as potential antipsychotic com-
pound, as a result of its good affinity and Meltzerꢁs ratio.
Acknowledgements
´
This work was supported by Spanish Comision Intermin-
isterial de Ciencia y Tecnologıa (CICYT) under Grants
´

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21. Data for selected compounds: 6a: oil. IR: 1681. H NMR
1
(CDCl3): d 1.52–1.64 (m, 2H); 1.72–2.10 (m, 6H); 2.13–2.44
(m, 4H); 2.61–2.74 (m, 2H); 2.92–2.98 (m, 4H); 6.95 (dt,
1H, J = 8.8, 2.0); 7.10–7.23 (m, 3H); 7.38 (t, 1H, J = 7.4);
7.58–7.71 (m, 1H); 7.91 (d, 1H, J = 7.8). MS (EI, m/z): 392
(M+). Hydrochloride: mp 243–244 °C. Anal. (C24H25FN2O2Æ
HClÆ1.5H2O): C, H, N. 6b: light orange solid, mp 121–
123 °C. IR: 1678. 1H NMR (CDCl3): d 1.64–1.70 (m, 2H);
2.04–2.14 (m, 6H); 2.22–2.53 (m, 4H); 2.60–2.77 (m, 2H);
2.96–3.08 (m, 4H); 3.84 (s, 3H); 7.04–7.09 (m, 2H); 7.16–
7.22 (m, 2H); 7.50 (d, 1H, J = 2.7); 7.67–7.69 (m, 1H). MS
(EI, m/z): 422 (M+). Hydrochloride: mp 239–240 °C. Anal.
C25H27FN2O3ÆHClÆ1/2H2O: C, H, N.
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