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.
abstract: 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.
authors.affiliation: Institut de Chimie Thérapeutique, Ecole de Pharmacie, Université de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Ooms
authors.forename: Johan
authors.initials: J
authors.lastname: Wouters
authors.forename: Olivier
authors.initials: O
authors.lastname: Oscari
authors.forename: Thierry
authors.initials: T
authors.lastname: Happaerts
authors.forename: Géraldine
authors.initials: G
authors.lastname: Bouchard
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Carrupt
authors.forename: Bernard
authors.initials: B
authors.lastname: Testa
authors.forename: Didier M
authors.initials: DM
authors.lastname: Lambert
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D002186:Cannabinoids / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D018360:Crystallography, X-Ray; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011869:Radioligand Assay; D051381:Rats; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D002186:Cannabinoids; D006827:Hydantoins; D008024:Ligands; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug