3-[[4-(4-Chlorophenyl)piperazin-1-yl]-methyl]-1H-pyrrolo[2,3-b]pyridine: An antagonist with high affinity and selectivity for the human dopamine D4 receptor

Full text of DOI:10.1021/jm9600712

J . Med. Chem. 1996, 39, 1941-1942
1941
Ta ble 1. Dopamine Receptor Subtype Affinity for Indoles and
7-Azaindoles
3-[[4-(4-Ch lor op h en yl)p ip er a zin -1-yl]-
m eth yl]-1H-p yr r olo[2,3-b]p yr id in e: An
An ta gon ist w ith High Affin ity a n d
Selectivity for th e Hu m a n Dop a m in e D4
Recep tor
J anusz J . Kulagowski,* Howard B. Broughton,
Neil R. Curtis, Ian M. Mawer, Mark P. Ridgill,
Raymond Baker, Frances Emms,
Stephen B. Freedman, Rosemarie Marwood,
Shil Patel, Smita Patel, C. Ian Ragan, and
Paul D. Leeson
Merck Sharp and Dohme Research Laboratories,
Neuroscience Research Centre, Terlings Park,
Eastwick Road, Harlow, Essex CM20 2QR, U.K.
Received J anuary 22, 1996
It is widely accepted that the dopaminergic system
plays a key role in the manifestation of schizophrenic
illness,1 a belief supported by the observation that all
clinically effective antipsychotic agents act as antago-
nists at the dopamine D2 receptor2 and that therapeuti-
cally relevant plasma concentrations of drug correlate
closely to their affinity for this site.3 Although classical
neuroleptics such as haloperidol 1 constitute first-line
antipsychotic therapy, their use is associated with
severe, mechanism-related side effects including induc-
tion of acute extrapyramidal symptoms (EPS), tardive
dyskinesia, and problems such as galactorrhea due to
increased prolactin release.4 In contrast, atypical an-
tipsychotics such as clozapine 2 present a lower inci-
dence of EPS, are effective in patients who are unre-
sponsive to classical agents and may also offer advan-
tages in treating the more resistant negative symptoms
of schizophrenia.5 The use of clozapine has, however,
a
Data are the mean of two to four independant determinations.
All new compounds were characterized by 1H NMR and mass
b
spectroscopy and gave satisfactory elemental analyses.
of clozapine correlate more closely to its affinity for the
D4 rather than D2 receptor, a property not shared by
other antipsychotic agents.13 Although controversial,14
an association between the D4 receptor and schizophre-
nia was recently suggested by Seeman,15 who found a
6-fold increase in D4 receptors in the caudate of schizo-
phrenic patients relative to controls. These intriguing
findings highlight the need for a selective ligand to aid
elucidation of the pharmacological role played by the
D4 receptor. In particular, a D4 receptor antagonist may
have potential as an antipsychotic devoid of the unde-
sirable side effects associated with agents in current use.
Our search for a selective D4 ligand commenced with
a topological similarity (TOPOSIM) search16 of the
Merck sample collection using a number of known
dopamine agonists and antagonists as probe structures.
Receptor binding was determined by displacement of
[3H]spiperone from cloned human receptors, D2 and D3
being stably expressed in CHO cells17 and D4 in HEK293
cells.18 This strategy led to the identification of the
indole 3 which exhibited modest selectivity for the D4
receptor (Table 1). In contrast, the unsubstituted
piperidine 4, also uncovered in the search, had no
significant affinity for the D4 receptor. This key finding
led us to examine a number of piperidines and related
cyclic amines substituted with lipophilic groups at the
4-position, while retaining the 3-indolylmethyl moiety
on nitrogen. The compounds were readily prepared in
45-73% yield by displacement of gramine 5 or 7-aza-
gramine 619 with the appropriate commercially available
amine in toluene or xylene at reflux (Scheme 1).
been compromised by a relatively high (up to 2%)
incidence of the potentially fatal blood disorder agranu-
locytosis,6 necessitating stringent monitoring of plasma
levels. The high affinity of clozapine for a wide range
of neurotransmitter receptors has frustrated attempts
to rationalize the improved clinical properties of this
drug.7 It has been postulated that a combination of D2
and 5-HT2 antagonism is responsible for the beneficial
properties of atypical neuroleptics,8 and compounds with
this profile, which will serve to support the hypothesis,
are now emerging.9 However, alternative approaches
have also been proposed,10 and the absence of a well-
defined, unequivocal mechanism of action for clozapine
has hitherto hampered the development of superior
antipsychotic agents.
The discovery of two new dopamine receptor subtypes,
designated D3 and D4, has elicited considerable interest
due to their close homology to the D2 receptor11 and the
disclosure of preferential binding of clozapine to the D4
receptor.12 Moreover, clinically relevant plasma levels
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1942 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 10
Communications to the Editor
Sch em e 1
12, a potential radioligand precursor, were also identi-
fied. The unique binding profile of 11 renders it an ideal
ligand with which to begin to unravel the biological
significance of the dopamine D4 receptor.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR and mass
spectral data for compounds 3, 4, and 7-12 (3 pages).
Ordering information is given on any current masthead page.
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Replacement of the 4-methyl group of 3 with phenyl
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all three receptors, although selectivity for the D4
receptor was reduced. Selectivity was restored with the
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improvement in affinity for the D4 receptor over 7, with
a corresponding reduction in D3 receptor binding.
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at the 4-position being optimum, as demonstrated by
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chain, changes were also made to the indole nucleus.
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tion of a further heteroatom by replacement of the indole
of 9 with 7-azaindole (1H-pyrrolo[2,3-b]pyridine). This
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ity, with 11 (L-745,870) having Ki of 0.43 and 960 nM
for D4 and D2 receptors, respectively, with considerably
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In conclusion, the modestly selective indole 3, identi-
fied by directed screening of the Merck sample library,
has been optimized to piperazinylazaindole 11, resulting
in a 1000-fold improvement in affinity for the D4
receptor and providing an antagonist with 2200- and
>5000-fold binding selectivity relative to D2 and D3
receptors, respectively. During the course of these
studies, the D2 selective ligand 10 and the iodo analogue
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