Design and synthesis of new benzimidazole-arylpiperazine derivatives acting as mixed 5-HT1A/5-HT3 ligands

Article abstract of DOI:10.1016/S0960-894X(03)00706-6

A series of new benzimidazole-arylpiperazine derivatives III were designed, synthesized and evaluated for binding affinity at serotoninergic 5-HT _1A and 5-HT₃ receptors. Compound IIIc was identified as a novel mixed 5-HT_1A

Full text of DOI:10.1016/S0960-894X(03)00706-6

Bioorganic & Medicinal Chemistry Letters 13 (2003) 3177–3180
Design and Synthesis of New Benzimidazole-Arylpiperazine
Derivatives Acting as Mixed 5-HT1A/5-HT3 Ligands
Marıa L. Lopez-Rodrıguez,a,* Bellinda Benhamu,a Ma Jose Morcillo,b
Ignacio Tejada,a David Avila,a Isabel Marco,a Lucio Schiapparelli,c
Diana Frechillac and Joaquın Del Rıoc
a
´
Departamento de Quımica Organica I, Facultad de Ciencias Quımicas, Universidad Complutense, E-28040 Madrid, Spain
´
´
Seccion de Quımica, Facultad de Ciencias, Universidad Nacional de Educacion a Distancia, E-28040 Madrid, Spain
b
´
´
Departamento de Farmacologıa, Facultad de Medicina, Universidad de Navarra, E-31008 Pamplona, Spain
´
c
´
Received 16 May 2003; revised 24 June 2003; accepted 1 July 2003
Abstract—A series of new benzimidazole-arylpiperazine derivatives III were designed, synthesized and evaluated for binding affinity
at serotoninergic 5-HT1A and 5-HT3 receptors. Compound IIIc was identified as a novel mixed 5-HT1A/5-HT3 ligand with high
affinity for both serotonin receptors and excellent selectivity over a1-adrenergic and dopamine D2 receptors. This compound was
characterized as a partial agonist at 5-HT1ARs and a 5-HT3R antagonist, and was effective in preventing the cognitive deficits
induced by muscarinic receptor blockade in a passive avoidance learning test.
# 2003 Elsevier Ltd. All rights reserved.
Introduction
In the course of a program aimed at the discovery of
new 5-HT1A and 5-HT3 agents, we have synthesized a
series of arylpiperazines17ꢀ22 I as potent 5-HT1A
R
The discovery of new ligands with affinity for the family
of serotonin receptors (5-HTRs) is an area of active
research in Medicinal Chemistry due to their involve-
ment in numerous physiological and pathophysiological
processes.1ꢀ4 At present seven classes of serotonin
receptors (5-HT1ꢀ7) including 14 subtypes have been
found,5,6 and most of them belong to the superfamily of
G protein-coupled receptors (GPCRs); only the 5-HT3R
is a ligand-gated cation channel receptor.7 Among 5-
HTRs, the 5-HT1A is involved in psychiatric dis-
orders8ꢀ11 such as anxiety, depression and memory loss.
On the other hand, 5-HT3R antagonists are of special
interest not only because of their wide clinical use as
antiemetic drugs in cancer patients,12,13 but also due to
their promising therapeutic potential in the treatment of
CNS disorders,14ꢀ16 such as anxiety, drug abuse and
withdrawal, and cognitive dysfuntion. In light of the
potential utility in anxiety and cognitive disorders of 5-
HT1A and 5-HT3 receptor ligands, it would be of inter-
est, in principle, the development of compounds with
affinity at both 5-HTR subtypes.
ligands and a class of azabicyclic benzimidazole deriva-
tives II which exhibited high affinity for the 5-HT3R23
(Fig. 1). In the present work, we have designed a series
of new mixed benzimidazole-arylpiperazines of general
structure III in which we have incorporated the struc-
tural elements of 5-HT1A and 5-HT3 pharmacophores
(Fig. 1). Among them, compound IIIc has shown high
affinity for both 5-HT1A and 5-HT3 receptors, and has
been characterized as a partial agonist at 5-HT1ARs and
a 5-HT3R antagonist with a potential interest in the
treatment of cognitive dysfunction.
Chemistry
The general procedure for the preparation of target
compounds III is shown in Scheme 1. Starting ben-
zimidazole carboxylic acids 1a–k were coupled with
(ꢁ)-3-aminoquinuclidine to afford the desired amides
IIIa–k. 2-[(4-arylpiperazin-1-yl)methyl]benzimidazole-
4-carboxylic acids 1a–k were obtained by reaction of
2-(chloromethyl)benzimidazole-4-carboxylic acid
with the corresponding arylpiperazine. The acid 3 was
prepared by condensation of 2,3-diaminobenzoic
3
*Corresponding author. Tel.:+34-913-944-239; fax:+34-913-944-103;
e-mail: mluzlr@quim.ucm.es
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00706-6

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Table 1. Binding data of compounds IIIa
Compd
Ar
KiꢁSEM
KiꢁSEM
(5-HT1A
)
(5-HT3)
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
IIIi
Phenyl
o-Methoxyphenyl
o-Ethoxyphenyl
o-Propoxyphenyl
o-isoPropoxyphenyl
o-Butoxyphenyl
>1000
23.1ꢁ1.5
10.3ꢁ1.1
27.2ꢁ0.9
24.6ꢁ3.2
62.1ꢁ1.3
15.1ꢁ4.8
23.9ꢁ2.9
18.3ꢁ0.4
24.0ꢁ1.0
32.5ꢁ5.3
>1000
149.8ꢁ33.4
18.0ꢁ1.7
56.1ꢁ2.2
34.4ꢁ3.0
45.9ꢁ3.5
>10,000
m-(Trifluoromethyl)phenyl
m-Chlorophenyl
Benzodioxan-5-yl
Naphth-1-yl
>10,000
467.1ꢁ14.0
IIIj
IIIk
>1000
147.8ꢁ6.7
Benzimidazol-4-yl
Figure 1. Structure of compounds I–III.
aValues are means of 2–4 experiments performed in triplicate.
(Table 1). The weak 5-HT1AR affinity of derivative IIIi
was unexpected, according to reported data for aryl-
piperazines bearing
a
benzodioxan-5-yl group.34,35
Additionally, all the compounds were selective over
a1-adrenergic and dopamine D2 receptors (Ki>1000–
10,000 nM). Compound IIIc was selected for further
pharmacological characterization due to its interesting
binding profile as mixed 5-HT1A/5-HT3 ligand with
high affinity for both receptors (5-HT1A: Ki=18.0
nM, 5-HT3: Ki=27.2 nM) (Table 1).
Scheme 1. Reagents and conditions: (a) 1,10-carbonyldiimidazole
(CDI), N,N-dimethylformamide (DMF), 40 ꢂC; (b) (ꢁ)-3-aminoqui-
nuclidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), DMF, 50 ꢂC; (c)
HOCH2COOH, HCl; (d) SOCl2, 80 ꢂC; (e) HCl/H2O, ꢀ; (f) arylpi-
perazine, acetonitrile, NEt3, 60 ꢂC.
Functional characterization of compound IIIc at 5-HT1A
and 5-HT3 receptors
The ability of compound IIIc to increase binding of
[35S]GTPgS to rat hippocampal membranes as well as
the antagonism to binding stimulated by the 5-
HT1AR agonist 8-OH-DPAT were evaluated.36 Com-
pound IIIc (10ꢀ10–10ꢀ7 M) induced minimal effects
on the basal binding of the GTP analogue. Only the
highest concentrations tested (10ꢀ6–10ꢀ5 M) produced
a moderate increase (20–28%) in [35S]GTPgS binding.
A much more marked stimulation was obtained in
acid24 with glycolic acid to give 2-(hydroxy-
methyl)benzimidazole-4-carboxylic acid 2,24 which was
treated with SOCl2 followed by hydrolysis. The non-
commercial arylpiperazines (Ar=o-ethoxyphenyl,25 o-
propoxyphenyl,26 o-isopropoxyphenyl,25 o-butoxy-
phenyl,25 naphth-1-yl,27 2,3-dihydro-1,4-benzodioxan-5-
yl,28 1-tritylbenzimidazol-4-yl)29 were synthesized
according to the literature.
the presence of the typical 5-HT1A
R
agonist
8-OH-DPAT (92% at 10ꢀ6 M). On the other hand,
compound IIIc blocked only partially the stimulation
of [35S]GTPg binding induced by 8-OH-DPAT at the
low concentrations of 10ꢀ10 and 10ꢀ9 M but not at
higher concentrations. The antagonism to 8-OH-
DPAT was considerably less pronounced than that
observed with the ‘silent’ 5-HT1AR antagonist WAY-
100635 (IC50=6 nM). The results obtained in the
[35S]GTPgS binding studies tend to suggest that
Pharmacology
Affinity data
Target compounds were assessed for in vitro binding
affinity at serotoninergic 5-HT1A and 5-HT3Rs by
radioligand binding assays, using [3H]-8-OH-DPAT30
and [3H]LY 278584,31 respectively, in rat cerebral
cortex membranes. The ligands were also evaluated
for in vitro affinity at a1-adrenergic receptors
compound IIIc behaves as
a partial agonist at
5-HT1ARs.
([3H]prazosin32)
and
dopamine
D2
receptors
Since it is known that 5-HT1AR agonists induce
hypothermia in rodents, the intrinsic effect of com-
pound IIIc on rectal temperature and on the
hypothermia response to the 5-HT1AR agonist 8-OH-
DPAT was also studied in mice.37 Compound IIIc (1
and 10 mg/kg) reduced body temperature by
approximately 1 ꢂC at 60 and 120 min after adminis-
tration, similar effects being obtained after either
dose. This compound did not significantly modify
([3H]raclopride33), in rat cerebral cortex and striatum
membranes, respectively. All the synthesized com-
pounds IIIa–k exhibited high 5-HT3R affinity
(Ki=10–62 nM) (Table 1), and derivatives with an o-
alkoxy group in the arylpiperazine ring have shown
nanomolar affinity for the 5-HT1AR (Ki=18–150 nM)
(Table 1). Only analogue IIIk is an exception in the
series (5-HT1A: Ki=147.8 nM, 5-HT3: Ki>1000 nM)

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and rather tended to potentiate the hypothermia
Conclusions
induced by 8-OH-DPAT (0.5 mg/kg sc). These in vivo
findings appear again to be consistent with a partial
agonism at 5-HT1ARs.
In summary, in a series of new benzimidazole-arylpi-
perazine derivatives compound IIIc has been identi-
fied as a novel mixed 5-HT1A/5-HT3 ligand with high
affinity for both serotonin receptors, an excellent
selectivity profile over a1-adrenergic and dopamine
D2 receptors, and an ability to counteract the cogni-
tive deficit induced by cholinergic blockade, suggest-
ing a potential interest in the treatment of cognitive
dysfunction.
The functional profile of compound IIIc at 5-HT3Rs
was characterized in the isolated longitudinal muscle–
myenteric plexus preparation from guinea-pig ileum.38
The contraction induced in this preparation by the
selective 5-HT3R agonist 2-Me-5-HT (10ꢀ5 M) was
inhibited by compound IIIc at concentrations 10ꢀ7
–
10ꢀ5 M, a full blockade of the contraction being
observed at the highest concentrations tested. Similar
effects were found with the typical 5-HT3R antagonist,
ondansetron. The IC50s for compound IIIc and ondan-
setron in this preparation were almost identical, 0.19
and 0.24 mM, respectively.
Acknowledgements
This work was supported by Ministerio de Ciencia y
Tecnologıa (BQU2001-1459). The authors are grateful to
U.N.E.D. for a predoctoral grant to I. Tejada and to
CEPA SCHWARZ PHARMA for a predoctoral grant to
I. Marco, who also thanks the Spanish Society of Ther-
apeutic Chemistry for the award of the ‘FAES’ prize.
Behavioural effects of compound IIIc
The anxiolytic-like effect of compound IIIc was eval-
uated by using a modified light–dark exploration test
in mice.39 In this modified procedure, control animals
spend less time in the white compartment on the
second day of exposure. This behaviour is effectively
prevented by administration of typical anxiolytic
drugs. At variance with the results obtained with
diazepam (1 mg/kg ip), which approximately doubled
the time spent in the white compartment, no sig-
nificant change was found after administration of
compound IIIc at doses of 0.1 and 1 mg/kg sc, given
30 min before the test, indicating no anxiolytic-like
effect for this compound in this test, at least at the
doses used.
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