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.
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.
Ooms
Frédéric
F
Institut de Chimie Thérapeutique, Ecole de Pharmacie, Université de Lausanne, CH-1015 Lausanne, Switzerland.
Wouters
Johan
J
Oscari
Olivier
O
Happaerts
Thierry
T
Bouchard
Géraldine
G
Carrupt
Pierre-Alain
PA
Testa
Bernard
B
Lambert
Didier M
DM
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
D002186:Cannabinoids; D006827:Hydantoins; D008024:Ligands; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug