Exploration of the pharmacophore of 3-alkyl-5-arylimidazolidinediones as new CB(1) cannabinoid receptor ligands and potential antagonists: synthesis, lipophilicity, affinity, and molecular modeling.
[en] A set of 29 3-alkyl 5-arylimidazolidinediones (hydantoins) with affinity for the human cannabinoid CB(1) 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 [(35)S]-GTP gamma S 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.
Disciplines :
Chemistry
Author, co-author :
Ooms, Frédéric ; Université de Liège - ULiège > HEC Liège Research > HEC Liège Research: Strategy & Performance for the Society ; Institut de Chimie Thérapeutique, Ecole de Pharmacie, Université de Lausanne, CH-1015 Lausanne, Switzerland
Wouters, Johan; Laboratoire de Chimie Moléculaire Structurale, Faculté des Sciences, Facultés universitaires Notre Dame de la Paix, B-5000 Namur, Belgium ; Institut de Recherches Microbiologiques Wiame, B-1070 Brussels, Belgium
Oscari, Olivier; Unité de Chimie pharmaceutique et de Radiopharmacie, Ecole de Pharmacie, Faculté de Médecine, Université catholique de Louvain, UCL-CMFA 7340, B-1200 Bruxelles, Belgium
Happaerts, Thierry; Unité de Chimie pharmaceutique et de Radiopharmacie, Ecole de Pharmacie, Faculté de Médecine, Université catholique de Louvain, UCL-CMFA 7340, B-1200 Bruxelles, Belgium
Bouchard, Géraldine; Institut de Chimie Therapeutique, Ecole de Pharmacie, Université de Lausanne, CH-1015 Lausanne, Switzerland
Carrupt, Pierre-Alain; Institut de Chimie Therapeutique, Ecole de Pharmacie, Université de Lausanne, CH-1015 Lausanne, Switzerland
Testa, Bernard; Institut de Chimie Therapeutique, Ecole de Pharmacie, Université de Lausanne, CH-1015 Lausanne, Switzerland
Lambert, Didier M; Unité de Chimie pharmaceutique et de Radiopharmacie, Ecole de Pharmacie, Faculté de Médecine, Université catholique de Louvain, UCL-CMFA 7340, B-1200 Bruxelles, Belgium
Language :
English
Title :
Exploration of the pharmacophore of 3-alkyl-5-arylimidazolidinediones as new CB(1) cannabinoid receptor ligands and potential antagonists: synthesis, lipophilicity, affinity, and molecular modeling.
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