Exploration of the pharmacophore of 3-alkyl-5-arylimidazolidinediones as new CB1 cannabinoid receptor ligands and potential antagonists: Synthesis, lipophilicity, affinity, and molecular modeling

Frédéric Ooms, Johan Wouters, Olivier Oscari, Thierry Happaerts, Géraldine Bouchard, Pierre Alain Carrupt, Bernard Testa, Didier M. Lambert

Research output: Contribution to journalArticle

Abstract

A set of 29 3-alkyl 5-arylimidazolidinediones (hydantoins) with affinity for the human cannabinoid CB1 receptor was studied for their lipophilicity and conformational properties in order to delineate a pharmacophore. These molecules constitute a new template for cannabinoid receptor recognition, since (a) their structure differs from that of classical cannabinoid ligands and (b) antagonism is the mechanism of action of at least three compounds (20, 21, and 23). Indeed, in the [35S]-GTPγS binding assay using rat cerebellum homogenates, they behave as antagonists without any inverse agonism component. Using a set of selected compounds, experimental lipophilicity was measured by RP-HPLC and calculated by a fragmental method (CLOGP) and a conformation-dependent method (CLIP based on the molecular lipophilicity potential). These approaches revealed two models which differentiate the binding mode of nonpolar and polar hydantoins and which could explain, at least for compounds 20, 21, and 23, the mechanism of action of this new family of cannabinoid ligands.

Original languageEnglish
Pages (from-to)1748-1756
Number of pages9
JournalJournal of Medicinal Chemistry
Volume45
Issue number9
DOIs
Publication statusPublished - 25 Apr 2002

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  • Datasets

    CCDC 197146: Experimental Crystal Structure Determination

    Bouchard, G. (Contributor), Carrupt, P. (Contributor), Happaerts, T. (Contributor), Lambert, D. M. (Contributor), Ooms, F. (Contributor), Oscari, O. (Contributor), Testa, B. (Contributor) & WOUTERS, J. (Contributor), Cambridge Crystallographic Data Centre, 1 Jan 2003

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