1: J Med Chem  2002 Apr 25;45(9):1748-56 

Erratum in:
 J Med Chem 2002 Oct 10;45(21):4799

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.

Ooms F, Wouters J, Oscari O, Happaerts T, Bouchard G, Carrupt PA, Testa B,
Lambert DM.

Institut de Chimie Therapeutique, Ecole de Pharmacie, Universite de Lausanne,
CH-1015 Lausanne, Switzerland.

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.

PMID: 11960486 [PubMed - indexed for MEDLINE]