Novel aminoethylbiphenyls as 5-HT7 receptor ligands

Article abstract of DOI:10.1016/j.bmcl.2007.03.054

The synthesis of a series of aminoethylbiphenyls as novel 5-HT₇ receptor ligands is described. The novel derivatives exhibit high affinity for the 5-HT₇ receptor with selectivity toward 5-HT_1A receptor.

Full text of DOI:10.1016/j.bmcl.2007.03.054

Bioorganic & Medicinal Chemistry Letters 17 (2007) 3018–3022
Novel aminoethylbiphenyls as 5-HT7 receptor ligands
a
a,
a
a
*
´ ´
Magalie Paillet-Loilier, Frederic Fabis, Alban Lepailleur, Ronan Bureau,
a
a
a
b
´
Sabrina Butt-Gueulle, Franc¸ois Dauphin, Aurelien Lesnard, Catherine Delarue,
Hubert Vaudryb and Sylvain Raulta
aCentre d’Etudes et de Recherche sur le Me´dicament de Normandie EA3915, Universite´ de Caen, UFR des Sciences Pharmaceutiques,
5, rue Vaube´nard 14032 Caen Cedex, France
bINSERM U413, IFRMP 23 Universite´ de Rouen, 76821 Mont-Saint-Aignan, France
Received 21 February 2007; revised 16 March 2007; accepted 19 March 2007
Available online 23 March 2007
Abstract—The synthesis of a series of aminoethylbiphenyls as novel 5-HT7 receptor ligands is described. The novel derivatives exhi-
bit high affinity for the 5-HT7 receptor with selectivity toward 5-HT1A receptor.
Ó 2007 Elsevier Ltd. All rights reserved.
The 5-HT7 receptor (5-HT7R) is the most recent subtype
identified of the serotonin (5-HT) receptor family.1
Application of molecular cloning has led to the identifi-
cation and the characterization of the 5-HT7 receptor
subtype from rat,2–5 mouse,6 human,7 guinea-pig8, and
pig.9 The 5-HT7 receptors have been located in the cen-
tral nervous system (thalamus, hypothalamus, hippo-
campus, cortex) and in peripheral tissues (pancreas,
spleen, coronary artery, ileum).3,5,7 Although biological
functions of these receptors are poorly understood, re-
cent reports suggest that 5-HT7 receptors are involved
in the pathophysiology of several disorders such as anx-
iety,10 depression,10,11 schizophrenia,12 control of circa-
dian rhythm,13 migraine,14 nociception,15 epilepsy,16
and relaxation of blood vessels.17 The 5-HT7 receptors
are also involved in different endocrine functions.18,19
We postulated that the 5-HT1AR affinity was due to the
presence of the 2-methoxyphenylpiperazine moiety,
which is a key fragment in many 5-HT1A receptor
ligands.22–25
We now wish to report our efforts in identifying a new
series of 5-HT7R ligands with good selectivity toward
the 5-HT1A receptor.
We analyzed the structural homology of the phenylpyr-
roles 6 with the fused polycyclic analogues 5 (left) and
aminotetralin (right) (Fig. 3).26,27 This led to a hypothe-
sis that simple phenylpyrroles 6 would be interesting
structures to investigate.
From these observations, we decided to synthesize a
series of phenylpyrroles bearing an ethylamine chain in
position 3 of the pyrrole (Scheme 1, compounds 9a–c
and 10a–b).
Several 5-HT7R ligands have been reported,20 including
aporphine analogues 120e and aminotetralins 2a–b20g
(Fig. 1).
These compounds were prepared from 7a–c21 as
outlined in Scheme 1. Nitrovinyl compounds 8a–c were
obtained by the reaction of nitromethane with aldehydes
7a–c, in the presence of ammonium acetate. Primary
amines 9a–c were prepared by reduction of nitrovinyl
8a–c with LiAlH4.28 Compounds 9a–b were then
subjected to Eschweiler–Clarke conditions, with formal-
dehyde and sodium cyanoborohydride in acetic acid, to
give the N,N-dimethyl derivatives 10a–b.29–31
We also recently described a novel series of phenylpyr-
roles as 5-HT7R ligands (Fig. 2).21 However, these com-
pounds were also potent ligands of the 5-HT1A receptor.
Keywords: Biphenyls; Serotonin; 5-HT7 receptors; 5-HT1A receptors;
Selectivity.
*
The results of binding assays on 5-HT74,5 and 5-HT1A
32
receptors are given in Table 1. Contrary to our
Corresponding author. Tel.: +33 2 3193 6458; fax: +33 2 3193
1188; e-mail: frederic.fabis@unicaen.fr
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.03.054

M. Paillet-Loilier et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3018–3022
3019
MeO
Me
OMe
MeO
OMe
Me
NC
Pr
N
N
N
1
2b
2a
Me
Pr
Me
Figure 1. 5-HT7 antagonist 1, 2a and agonist 2b of the aporphine and 2-aminotetralin series.
hypothesis, the 5-HT7R affinity was not improved by
shifting the ethylamine chain from position 2 to position
3 of the pyrrole and alkylation of the amino group did
not result in an increase in affinity (compounds 10a–b).
However, these compounds showed no affinity for the
5-HT1A receptor. These results support the hypothesis
that the 2-methoxyphenylpiperazine moiety could be
responsible for the lack of selectivity.
R
N
N
OMe
N
3a R = 2-Me; 5-HT7 Ki = 4.7 nM; 5-HT1A Ki = 9.9 nM
3b R = 2-CN; 5-HT7 Ki = 5.4 nM; 5-HT1A Ki = 33.7 nM
3c R = 2-Me, 6-CO2Me; 5-HT7 Ki = 18nM; 5-HT1A Ki = 18.5 nM
In order to better align with both phenylaporphine and
aminotetraline compounds, we chose to replace the pyr-
role by a second phenyl group.
Figure 2. Phenylpyrroles 3a–c as novel 5-HT7 receptor ligands.
OH
Me
NC
Me
Sybil
N
5
N
N
4
Me
1
Me
Me
N
NH2
6
Figure 3. Alignment between phenylpyrrole 6 and phenylaporphine 5 (left) or aminotetralin (right).
R
R
R
R
N
N
N
N
(ii)
(iii)
(i)
Me
CHO
NO2
NH2
N
7a-c
9a-c
10a-b
8a-c
Me
Scheme 1. Reagents and conditions: (i) 2.5 equiv ammonium acetate, CH3NO2, reflux, 5 h, 80–99%; (ii) 4 equiv LiAlH4, THF, reflux, 4 h, 81–94%;
(iii) 2.7 equiv NaBH3CN, 4 equiv HCHO, AcOH, MeOH, rt, 8 h, 42%.

3020
M. Paillet-Loilier et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3018–3022
Table 1. Human 5-HT7 receptor and rat 5-HT1A affinities of compounds 9a–c and 10a–ba
Compound
R
5-HT7 % Inhib.
5-HT1A % Inhib.
10À6 M
10À8 M
10À6 M
10À8 M
9a
9b
2-CH3
62
0
5
0
16
0
0
0
2,4,6-CH3
2,3-CH3
2-CH3
9c
48
87
56
25
16
3
17
41
20
0
10a
10b
14
0
2,4,6-CH3
a 5-HT7 receptors and radioligand used in binding assays: human cloned receptors in sf9 cells, [3H]LSD, according to Refs. 4 and 5. Binding
experiments on 5-HT1A receptors were realized according to Hall et al.’s procedure.32
The series of aminoethylbiphenyls were synthesized
from the commercially available 3-bromophenethyla-
mine 11. N,N-dimethylation of the primary amine 11,
followed by Suzuki cross-coupling reactions, afforded
the target compounds 12a–i (Scheme 2). Boc-protection
of 11, followed by Suzuki cross-coupling reactions and
acidic hydrolysis, led to compound 13.
of ortho substituents (Me or OMe) into the phenyl ring
A increased the 5-HT7R affinity (12b and 12c) as de-
scribed for other 5-HT7 ligands.20e,g,h Moreover, these
ortho substituted compounds showed a good selectivity
toward 5-HT1A receptor. The presence of a substituent
in ortho position was essential for the 5-HT7R affinity.
We can hypothesize that the aryl groups A and B should
not be placed in the same plane. The distributions of the
dihedral angle between the two phenyl rings, not substi-
tuted and ortho substituted, were analyzed from CSD
data.36 The results showed clearly a different distribu-
tion between the two fragments (values of 0° highly
probable without substitution and around 45° for ortho
substituted). So, these results (compounds 12e–i) sup-
port this hypothesis.
Compound 15 was obtained from the commercially
available 3-bromophenylacetonitrile 14 after hydroly-
sis,33 reduction34, and amination by morpholine via
the mesylate.35 The Suzuki cross-coupling reaction
between 2,6-dimethoxyphenylboronic acid and 15 led
to 16 (Scheme 2).
These novel biaryls were evaluated for their affinity for
the 5-HT7 and 5-HT1A receptors, according to methods
previously described4,5,32 and the results are summarized
in Table 2.
Introduction of a second substituent in ortho position
does not modify the 5-HT7R affinity (12a, 12d) but im-
proves the selectivity toward the 5-HT1A receptor. In-
deed, the 5-HT1A/5-HT7 affinity ratio is around 60 for
compounds 12b and 12c, and increased respectively to
400 and 600 when we introduced a second substituent
in ortho position of the phenyl group (12a and 12d).
In this series, the 5-HT7 affinity and selectivity depend
on the substitution of the phenyl ring A. Introduction
In addition, we observed that an increase of the steric
hindrance on the basic nitrogen atom led to inactive
compound (compare 16 and 12a), whereas the free ami-
no group was tolerated (compare 13 and 12b). Other
compounds will be synthesized to confirm this
observation.
Ar
(i),(ii)
B
Me
Br
N
12a-i
Me
Ar
NH2
11
(iii),(iv),(v)
B
Compounds 12a and 12b were then evaluated for their
pharmacological profile by using a specific test of aldo-
sterone secretion from perifused rat adrenal cortex
stimulated by serotonin through 5-HT7R.37,38 Com-
pound 12b behaved as 5-HT7 antagonist with calcu-
lated pKb value of 7.03. In contrast, compound 12a
was found to be a partial agonist with no antagonistic
profile.
NH2
13
A
OMe
Br
Br
MeO
(vi)-(ix)
(x)
B
CN
N
N
14
15
16
From our initial series of phenylpyrroles, with a moder-
ate 5-HT7 affinity, we obtained a new series of com-
pounds with high 5-HT7 affinity by replacement of the
pyrrole cycle by a second phenyl cycle. Furthermore, a
good selectivity toward 5-HT1A receptor was observed
for most of these compounds, in particular for the dior-
tho substituted compounds.
O
O
Scheme 2. Reagents and conditions: (i) 2.7 equiv NaBH3CN, 4 equiv
HCHO, AcOH, MeOH, rt, 8 h, 77%; (ii) 1.8 equiv ArB(OH)2, 5%
(PPh3)4Pd, Tol/EtOH 9:1, 2.5 equiv Na2CO3, reflux, 24 h, 49–89%; (iii)
1.1 equiv (Boc)2O, 2.5 equiv TEA, THF, N2, rt, 12 h, 77%; (iv) 1.8
equiv ArB(OH)2, 5% (PPh3)4Pd, Tol/EtOH 9:1, 2.5 equiv Na2CO3,
reflux, 24 h, 84%; (v) HCl, Et2O, rt, 12 h, 61%; (vi) 3 equiv LiOH,
MeOH/H2O 3:1, 50°C, 72 h, 78%; (vii) 2 equiv BH3.THF 1M, THF,
0°C, 4 h, 93%; (viii) 1.2 equiv CH3SO2Cl, Pyridine, rt, 12 h, 65%; (ix) 4
equiv morpholine, DMF, reflux, 24 h, 72%; (x) 2 equiv ArB(OH)2, 5%
(PPh3)4Pd, Tol/EtOH 9:1, 4.5 equiv Na2CO3, reflux, 24 h, 36%.
These results show that aminoethylbiphenyles could be
considered as interesting simplified structures of the phe-
nylaporphine 5, with an easier synthetic access.

M. Paillet-Loilier et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3018–3022
3021
Table 2. Binding affinities of compounds 12a–i, 13, and 16 to human 5-HT7 and rat 5-HT1A receptorsa
Compound
Ar (A)
5-HT7 % Inhib.
10À6 M/10À8 M
Ki
(nM)c
5-HT1A % Inhib.
10À6 M/10À8 M
Ki
(nM)c
12a
12b
12c
12d
12e
12f
12g
12h
12i
13
2,6-DiMeOPh
2-MePh
100/50
81/72
69/23
93/73
70/18
52/9
8.6
7.6
18/3
85/1
4826
443
2-MeOPh
2,6-DiMePh
Ph
8.4
48/12
33/6
18/2
531
6.2
2250
ND
ND
ND
ND
ND
1470
ND
NDb
ND
ND
ND
ND
7.5
4-MeOPh
3,4-DiMeOPh
2-Thienyl
3-Thienyl
2-MePh
37/0
52/12
63/6
38/0
75/12
87/12
92/71
9/0
64/20
37/0
14/7
16
2,6-DiMeOPh
ND
a 5-HT7 receptors and radioligand used in binding assays: human cloned receptors in sf9 cells, [3H]LSD, according to Refs. 4 and 5. Binding
experiments on 5-HT1A receptors were realized according to Hall et al.’s procedure.32
b Not determined.
c The Ki-values are means of three experiments.
17. Jahnichen, S.; Glusa, E.; Pertz, H. H. Naunyn-Schmiede-
berg’s. Arch. Pharmacol. 2005, 371, 89.
18. Jørgensen, H.; Riss, M.; Knigge, U.; Kjaer, A.; Warberg,
J. J. Neuroendocrinol. 2003, 15, 242.
In conclusion, we have identified new leads in the search
of 5-HT7R ligands with antagonist or partial agonist
profile. The best compounds 12a and 12b will be submit-
ted to further pharmacological studies.
19. Louiset, E.; Contesse, V.; Groussin, L.; Cartier, D.;
Duparc, C.; Barrande, G.; Bertherat, J.; Vaudry, H.;
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