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.
Subject(s)
Cannabinoids/metabolism , Hydantoins/chemical synthesis , Receptors, Drug/metabolism , Animals , Binding, Competitive , CHO Cells , Cerebellum/metabolism , Chromatography, High Pressure Liquid , Cricetinae , Crystallography, X-Ray , Humans , Hydantoins/chemistry , Hydantoins/metabolism , In Vitro Techniques , Ligands , Models, Molecular , Molecular Conformation , Radioligand Assay , Rats , Receptors, Cannabinoid , Receptors, Drug/antagonists & inhibitors , Receptors, Drug/chemistry , Structure-Activity RelationshipABSTRACT
The enantioseparation of eighteen new chiral hydantoin derivatives was studied on three different polysaccharide type chiral stationary phases (CSP) Chiralpak AD, Chiralcel OD and Chiralcel OJ in the normal-phase HPLC mode. Chiralpak AD material exhibited the most universal chiral resolving ability and allowed the enantioseparation of 17 out of 18 compounds followed by Chiralcel OD (10 enantioseparations of 12 tested compounds) and Chiralcel OJ (eight enantioseparation from 13 tested analytes). Some complementary separations were observed and all of 18 compounds could be resolved at least with one of the three chiral CSP under the conditions of this study. With regard to the structure of the analytes, bulky electron rich substituents at C5 of the hydantoin nucleus appear to favor stereoselective interactions.
