Synthesis and in vitro binding studies of substituted piperidine naphthamides. Part II: Influence of the substitution on the benzyl moiety on the affinity for D2L, D4.2, and 5-HT2A receptors

Article abstract of DOI:10.1016/j.bmcl.2006.12.106

In continuation of our work on N-(piperidin-4-yl)-naphthamides, the effect of substituted benzyl groups on D_2L, D_4.2, and 5-HT_2A receptor affinity was evaluated. In the 1-naphthamide series most compounds were highly selective for D_4.2 over D_2L and 5-HT_2A receptors. Halogen and methyl substitution in position 3 or 4 of the benzyl group increased D_4.2 affinity. In the 2-naphthamide series a similar high D_4.2 over D_2L selectivity was retained while 5-HT_2A affinity was increased. 3-Methoxy, 3-methyl, and 4-methyl substituents were favorable for D_4.2 affinity while halogens reduced affinity. 2-Naphthamides with a 3-bromo- or a 3-methyl group were mixed D_4.2/5-HT_2A ligands similar to their unsubstituted parent compound. All compounds from both series with significant affinity for D_4.2 and 5-HT_2A receptors were antagonists.

Full text of DOI:10.1016/j.bmcl.2006.12.106

Bioorganic & Medicinal Chemistry Letters 17 (2007) 1570–1574
Synthesis and in vitro binding studies of substituted piperidine
naphthamides. Part II: Influence of the substitution on the benzyl
moiety on the affinity for D2L, D4.2, and 5-HT2A receptors
Pascal Carato,a Amaury Graulich,b Niels Jensen,c
c
b,
*
´
Bryan L. Roth and Jean-Franc¸ois Liegeois
aLaboratoire de Chimie The´rapeutique, Universite´ du Droit et de la Sante´ Lille II, rue du Professeur Laguesse 3,
BP83, F-59006 Lille, France
b
` ˆ
Drug Research Center, Laboratory of Medicinal Chemistry, University of Liege, avenue de l’Hopital, 1 (B36),
`
B-4000 Liege 1, Belgium
cDepartment of Pharmacology School of Medicine and Division of Medicinal Chemistry and Natural Products, School of Pharmacy,
University of North Carolina Chapel Hill Medical School, 8032 Burnett-Womack Building, CB# 7365, Chapel Hill, NC 27599, USA
Received 24 November 2006; revised 20 December 2006; accepted 26 December 2006
Available online 8 January 2007
Abstract—In continuation of our work on N-(piperidin-4-yl)-naphthamides, the effect of substituted benzyl groups on D2L, D4.2
,
and 5-HT2A receptor affinity was evaluated. In the 1-naphthamide series most compounds were highly selective for D4.2 over
D2L and 5-HT2A receptors. Halogen and methyl substitution in position 3 or 4 of the benzyl group increased D4.2 affinity. In the
2-naphthamide series a similar high D4.2 over D2L selectivity was retained while 5-HT2A affinity was increased. 3-Methoxy, 3-methyl,
and 4-methyl substituents were favorable for D4.2 affinity while halogens reduced affinity. 2-Naphthamides with a 3-bromo- or a
3-methyl group were mixed D4.2/5-HT2A ligands similar to their unsubstituted parent compound. All compounds from both series
with significant affinity for D4.2 and 5-HT2A receptors were antagonists.
Ó 2007 Elsevier Ltd. All rights reserved.
Clozapine profoundly modified the concept of antipsy-
chotic drugs a few decades ago and, due to several side
effects, has also stimulated the search for safer and more
effective antipsychotics. The discovery of new and safer
antipsychotic drug is still an enormous challenge in the
treatment of psychotic disorders.1–4 Although some
compounds have been marketed during the last decade,
progress is slow, also caused by the fact that the molec-
ular and cellular mechanisms underlying the develop-
ment of schizophrenia remain unclear.5 Taking into
account some structural features of clozapine, we have
developed a first series of compounds based on N-(pip-
eridin-4-yl)- and N-(piperidin-1-yl)-naphthamide tem-
plate.6 Clozapine can be characterized by two
structural parameters: as a basic nitrogen and an
electronically rich aromatic ring separated by a distance
that the position of the amide linkage has a significant
influence on the binding to the tested receptors.
N-(1-benzyl-piperidin-4-yl) derivatives were found to
be superior compared to their 4-substituted amino-
piperidin-1-yl analogues when tested for binding to
D4.2 and 5-HT2Areceptors. Therefore, we have focused
our further chemical effort on the N-(1-benzyl-piperi-
din-4-yl) series.
In this publication, we report the preparation and the
in vitro D4.2, D2L, and 5-HT2A binding of a series of
substituted benzyl analogues of N-(1-benzylpiperidin-
4-yl)-1-naphthamide (1) or N-(1-benzylpiperidin-4-yl)-
2-naphthamide (2). Intrinsic activity was tested for
compounds presenting a significant affinity for these
receptor sites.
7
˚
of 7.72 A. In the first part of this work, we have found
The synthesis of these compounds was accomplished
by the sequence of reactions outlined in Scheme 1.
1-Naphthoyl chloride or 2-naphthoyl chloride in ethyl
acetate was reacted with 4-amino-1-benzyl-piperidine
to afford N-(1-benzylpiperidin-4-yl)-1-naphthamide (1)
Keywords: D4.2 receptors; 5-HT2A receptors; Antagonist;Schizophrenia.
*
Corresponding author. Tel.: +32 43 66 43 77; fax: +32 43 66 43 62;
e-mail: JF.Liegeois@ulg.ac.be
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.12.106

P. Carato et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1570–1574
1571
N
O
O
Cl
NH
a
1,2
O
b
NH
N
O
NH
R
c
NH
5-37
3,4
Scheme 1. Reagents and conditions: (a) 4-amino-1-benzylpiperidine, EtOAc, Et3N; (b) 10% Pd/C, ammonium formate, MeOH; (c) R–C6H4–CH2–Cl
or C5H4N–CH2–Cl, KI, Et3N, anhydrous acetone. 1- and 2-Naphthamide derivatives: R = H (1,2), 2-Cl (5,20), 3-Cl (6,21), 4-Cl (7,22), 2-Br (8,23),
3-Br (9,24), 4-Br (10,25), 3-CF3 (11,26), 4-CF3 (12,27), 2,3,4,5,6-F (13,28), 4-NO2 (14,29), 3-MeO (15,30), 4-MeO (16,31), 2-Me (17,32), 3-Me
(18,33), 4-Me (19,34).
or N-(1-benzylpiperidin-4-yl)-2-naphthamide (2). These
compounds were used for preparing other compounds
in the series. N-(1-Benzylpiperidin-4-yl)-1-naphthamide
(1) was first debenzylated with ammonium formate
and Pd/C in refluxing methanol to give the correspond-
ing N-(piperidin-4-yl)-1-naphthamide (3). N-(1-Ben-
zylpiperidin-4-yl)-2-naphthamide (2) was debenzylated
under 10 bar hydrogen in the presence of Pd/C to give
N-(piperidin-4-yl)-2-naphthamide (4). Amines (3-4) were
alkylated by using the appropriate benzyl halide under
basic conditions to give the corresponding N-substituted
benzyl analogues (5–37).
sus D2L and 5-HT2A sites. In comparison with the corre-
sponding unsubstituted derivative (1), the presence of a
substituent such as a chloro (6, 7), bromo (9, 10), trifluo-
romethyl (11, 12) or methyl group (17–19) in position 3
or 4 of the benzyl moiety increased the affinity for D4.2
receptors. A nitro group in position 4 (14) was not tol-
erated. A methoxy group either in position 3 or 4 (15,
16) did not seem to be favorable. An electron withdraw-
ing substituent in position 2 of the benzyl moiety (5,8)
reduced D4.2 affinity. The pentafluoro substituent (13)
was unfavorable.
In 2-naphthamide series, a mixed D4.2 and 5-HT2A pro-
file was observed. The unsubstituted (2), the 3-bromo
(24) or the 3-methyl (33) derivatives were the most
potent. For further in vivo biological evaluation the
substituted derivatives (24,33) have a lower solubility
which can be a drawback. In this series, the affinity for
5-HT2A sites was more affected by the substitution on
the benzyl moiety than the D4.2 affinity. The presence
of a nitro group in position 4 (29) was better tolerated
than in the 1-naphthamide series. The pentafluoro sub-
stitution (28) was not favorable. The replacement of
the aromatic ring by a pyridine was deleterious whatever
the position of the pyridine nitrogen was.
The affinity of compounds for cloned human D4.2 and
D2L, and native rat 5-HT2A receptors was evaluated in
in vitro binding assays using the radioligands [3H]nemo-
napride, [3H]spiperone, and [3H]ketanserin, respectively,
according to previously described procedures.8 An ini-
tial screen at 1 lM was performed and drugs which
had significant activity (>50% inhibition) had detailed
inhibition isotherms performed and Ki values calculated
according to the Cheng–Prusoff equation.9 The in vitro
receptor binding data are reported in Tables 1 and 2.
Compounds with significant affinity were tested for ago-
nistic effects at D4.2 and 5-HT2A receptors as described
previously.6 Antagonism was further verified at a con-
centration of 5 lM in the presence of 500 nM dopamine
for D4.2receptors and 100 nM serotonin for 5-HT2A
receptors.
In functional assays for determining intrinsic activity on
D4.2 and 5-HT2A receptors, all tested compounds (see
Tables 1 and 2) had no agonistic activity. The antago-
nism of these compounds was further verified by co-ap-
plication with the respective agonists. All tested
compounds blocked the effects of dopamine and seroto-
nin at the respective receptors. This is in agreement with
their binding affinities together with their absence of
agonism.
None of the compounds had appreciable affinity for D2L
receptors. Unsubstituted N-benzyl derivatives (1,2) pos-
sessed moderate to high affinity for D4 receptors with
negligible affinity for D2L receptors, while compound 2
had additional affinity for 5-HT2A receptors.
In this series of compounds a clear difference in binding
to D4.2 and 5-HT2A receptors was observed between the
1- and 2-naphthamide series. Several 1-naphthamide
derivatives had a significant selectivity for D4.2 sites ver-
The present chemical modifications did not increase D2L
affinity. The absence of an ortho-methoxy group in the
vicinity of the carboxamide group in the previous series
leads to a reduction in the affinity for D2L sites in

1572
P. Carato et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1570–1574
accordance with previous data.10,11 This reduction was
not necessarily due to the basic side chain as we have
previously found in a pyridobenzodiazepine series that
an 4-amino-1-benzyl-piperidine side chain leads to mol-
ecules with significant D2L, D4.2, and 5-HT2A receptor
affinity.8 Therefore, if an increase of D2 affinity is need-
ed, it is suggested to prepare the respective ortho-meth-
oxy derivatives. The degree of D2 receptor blockade
needed for antipsychotic activity still remains unknown.
Clozapine, for instance, is a weak D2 blocker but pos-
sesses a clear anti-schizophrenic potential. Neuroimag-
ing studies have shown that an optimal D2 receptor
occupancy of 60–70% is sufficient to produce an atypical
antipsychotic effect.12–14 If D2 receptor occupancy is too
high, the atypical profile can be lost even in the presence
of high 5-HT2 occupancy.14 Dopamine and serotonin
systems have been implicated in the pathophysiology
of schizophrenia and other psychotic disorders. The
high affinity of clozapine for the D4 and 5-HT2A recep-
tor versus the D2 receptor contributes to a low risk of
extrapyramidal side effects. The development of D4 li-
gands for treating schizophrenia failed particularly when
evaluating the efficacy of L-745,87015or, more recently,
sonepiprazole.16 In some cases, agonist activity was
detected and could be the explanation for low efficien-
cy.17,18 However, D4 receptors may act in synchrony
with other neurotransmitter receptors to mediate, at
least in part, the beneficial therapeutic effects of several
Table 1. In vitro binding affinities of substituted N-(1-benzylpiperidin-
4-yl)-1-naphthamides for D2L, D4.2, and 5-HT2A receptors
O
N
N
H
R
a
a
a
Compound
R
D4.2
5-HT2A
D2L
1
5
H
162 48b
329 214b
116 18b
43 19b
35%
>1000b
—
>1000
—
2-Cl
3-Cl
4-Cl
2-Br
3-Br
4-Br
3-CF3
4-CF3
6
49%
23%
—
462 93b
—
—
0%
0%
8%
—
7
8
9
66 35b
44 2b
10
11
12
13
14
15
16
17
18
19
4%
0%
0%
0%
0%
0%
3%
9%
11%
13%
119 18b
96 13b
0%
32%
228 62
20%
23%
—
2,3,4,5,6- F
4-NO2
3-MeO
4-MeO
2-Me
42%
168 40b
223 74b
155 30b
77 16b
69 15b
26%
38%
33%
3-Me
4-Me
a Ki (in nM; means SD; n P 2 if unspecified) or percentage of inhi-
bition at 1 lM.
b The compound had no agonistic activity in functional assays and
blocked the effect of 100 nM serotonin (5-HT2A receptors) or 500 nM
dopamine (D4.2 receptors).
Table 2. In vitro binding affinities of substituted N-(1-benzylpiperidin-4-yl)- and N-(1-(pyridylmethyl)-piperidin-4-yl)- 2-naphthamides for D2L, D4.2
and 5-HT2A receptors
,
R
N
O
N
N
O
N
H
NH
2-34
35-37
a
a
a
Compound
R
D4.2
5-HT2A
44 5b
D2L
2
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
H
2-Cl
11 1b
48%
54 4b
37 4b
31%
36 19b
34 11b
103 48b
>1000
0%
133 18b
133 2b
242 50b
47%
53 10b
223 60b
15%
3-Cl
4-Cl
29%
15%
0%
2-Br
3-Br
4-Br
3-CF3
4-CF3
—
—
9%
0%
84
7
36%
2,3,4,5,6- F
4-NO2
0%
4%
0%
0%
181 55b
16 2b
31 4b
26 4b
11 6b
21 4b
278 112b
158 8b
151 37b
175 28b
87 13b
222 68b
545 175
524 105
695 172
3-MeO
4-MeO
2-Me
0%
18%
6%
3-Me
4-Me
20%
42%
5%
2-Pyridyl
3-Pyridyl
4-Pyridyl
299
8
326 78
32%
4%
5%
a Ki (in nM; mean SD; n P 2 if unspecified) or percentage of inhibition at 1 lM.
b The compound had no agonistic activity in functional assays and blocked the effect of 100 nM serotonin (5-HT2A receptors) or 500 nM dopamine
(D4.2 receptors).

P. Carato et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1570–1574
1573
antipsychotics in patients with schizophrenia and other
Acknowledgments
psychotic disorders. Indeed, an involvement of D4
receptors in hippocampal neurons’ activity by depress-
ing N-methyl-D-aspartate (NMDA) receptor activity
through the activation of platelet-derived growth factor
receptors was reported.19 An inhibition of glutamatergic
signaling in the frontal cortex was also shown.20 Both
effects tend to link this receptor and the glutamate
signaling system which has been clearly associated
with cognition. The evaluation of the mixed D4/5-HT2A
ligand fananserin in schizophrenic patients was
unsuccessful.21 Nevertheless, the role of these receptors’
needs to be clarified since it has been shown that chronic
clozapine or related antipsychotics increase D4 receptors
density and decrease 5-HT2A receptor density in brain
areas involved in psychotic disorders.22–24
The technical assistance of Y. Abrassart, S. Counerotte
is gratefully acknowledged. A.G. is a Research Fellow of
`
the ‘Fonds pour la formation a la Recherche Industrielle
et Agricole (F.R.I.A.)’. J.F.L. is a Senior Research
Associate of the ‘Fonds National de la Recherche Scien-
tifique de Belgique (F.N.R.S.)’. P.C. was supported by a
`
post-doctoral fellowship of the University of Liege.
Functional data were generously provided in the context
of the National Institute of Mental Health’s Psychoac-
tive Drug Screening Program (NIMH PDSP) Contract
NO1MH32004.
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FANANSERIN
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In summary, the naphthamides presented in this and the
previous article act as antagonists at D4.2 and 5-HT2A
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