Synthesis and D2-like binding affinity of new derivatives of N-(1-ethyl-2-pyrrolidinylmethyl)-4,5-dihydro-1H-benzo[g]indole-3-carboxamide and related 4H-[1]benzothiopyrano[4,3-b]pyrrole and 5,6-dihydro-4H-benzo[6,7]cyclohepta[b]pyrrole-3-carboxamide analogues
A new series of 2-aminomethylpyrrolidinyl-derived 4,5-dihydrobenzo[g]indole-3-carboxamides and related compounds 2 were synthesized and evaluated for their ability to bind to dopamine D2-like receptors in vitro. Among these compounds 2k (X=CH2–CH2, R=Cl, R1=H), in behavioural tests in rats, has shown reduced hyperactivity at a dose which failed to induce catalepsy.
Introduction
Dopamine receptors can be divided into two major families: the D1-like and D2-like receptors based on their pharmacological profiles and coupling with the enzyme adenylate cyclase.1 Molecular cloning techniques have shown that the D1-like family is further divided into D1 and D5 receptors, both activating adenylate cyclase, while the D2-like family is divided into D2, D3 and D4 receptors, which either inhibit cyclic adenosine monophosphate (cAMP) production or are not coupled to adenylate cyclase.2 Psychotic disorders, such as schizophrenia, seem to be characterized by an overactivity of dopamine-secreting neurons in the ‘limbic brain’, rich in D2-like receptors.3 From a pharmacological point of view, D2 receptor antagonists can be used to treat these diseases effectively; however, a long term treatment is associated with the induction of disabling side-effects such as extrapyramidal syndrome (EPS) and irreversible tardive dyskinesia. The therapeutic benefit of D2 antagonists in treating psychotic disorders has been fully accepted with the discovery of more effective antipsychotic drugs characterized by minimal induction of extrapyramidal effects (atypical antipsychotics).3 Therefore, the synthesis of novel antipsychotics with a better pharmacological profile remains a primary goal in the research for the therapy of psychoses.3
In previous papers,4, 5 we have reported the synthesis and structure–activity relationships of a series of 5-phenylpyrrole-3-carboxamides (I) and related 4,5-dihydrobenzo[g]indole-3-carboxamides (II) analogues whose most representative terms were 1a and 2a, respectively (Fig. 1).
Encouraged by these results, we carried out several modifications of 2a. A first objective of this study was to seek correlations between the electronic and hydrophobic properties of the benzene and pyrrole substituents as well as to evaluate the bioisosteric replacement CH2 to S in the ethylenic bridge with a view to determine those physicochemical parameters which contribute to D2-like binding affinity. Moreover, the spatial arrangement of the two aryl/heteroaryl rings of 2a would be expected to influence bioactivity profoundly; thus, the preparation of 5,6-dihydro-4H-benzo[6,7]cyclohepta[b]pyrrole analogues was also contemplated and their biological evaluation should permit some understanding of the importance of the relative positions of the aryl/heteroaryl rings. In summary, therefore, the synthesis of the new benzo[g]indole-3-carboxamide derivatives and related compounds, 2b–k and their in vitro binding to the dopamine D2-like receptors are reported in the present paper.
Finally, we performed a preclinical study on the potential antipsychotic activity of compound 2k. To this end we studied the effect of 2k on a behavioural test which is considered to be predictive of antipsychotic activity: the antagonism of amphetamine-induced hyperactivity in rats.6 Moreover, since affinity for D2-like receptors is related also to the ability of antipsychotics to cause extrapyramidal side effects, we compared the effect of different doses of compound 2k to that of the classical antipsychotic haloperidol on the horizontal bar-inclined grid test in rats, a test which provides an index of catalepsy, an effect which is extrapyramidal in nature and is predictive of extrapyramidal side effects in humans.7
Section snippets
Chemistry
Target compounds 2b–k were prepared as shown in Scheme 1. The acids 6, prepared via the esters 5 by saponification, were activated with 1,1′-carbonyldiimidazole, and without isolation, the intermediate N-imidazolides were reacted with a stoichiometric amount of the 2-aminomethyl-1-ethylpyrrolidine.
Esters 5b–f, 5i–j were prepared, as recently reported by us for 5a5 and 5g,5 via thermal cyclization of the O-vinyl oximes 4,8 in turn obtained by Michael addition of ketoximes 3 upon methyl
Receptor binding
The target carboxamide analogues of 2a, 2b–k, were examined in vitro for their binding affinities to dopamine D2-like receptors. Affinities for the dopamine sites were determined via standard competitive displacement assay using D2-like receptors isolated from caudate nucleus of male Sprague–Dawley rats with [3H]YM-09151–2 (nemonapride) as a specific ligand14 and (−)-raclopride as a specific displacer.15 The dopamine D2-like receptor binding affinities of the carboxamides 2b–k are listed in
Chemistry
General information. Unless otherwise noted, all materials were obtained from commercial suppliers and used without purification. Anhydrous solvents such as ethanol (EtOH), tetrahydrofuran (THF) and dimethyl-formamide (DMF) were obtained from Aldrich in sure-seal bottles.
All reactions involving air-or moisture-sensitive compounds were performed under an argon ‘S’ atmosphere. Flash chromatography was performed using Merck Silica gel 60 (230–400 mesh ASTM).
Thin-layer chromatography (TLC) was
Acknowledgements
The authors acknowledge Professor G. Cignarella for his insightful comment on this work and Dr. E. Maciocco for binding data.
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