Synthesis and Activity of 1,3,5-Triphenylimidazolidine-2,4-diones and 1,3,5-Triphenyl-2-thioxoimidazolidin-4-ones: Characterization of New CB1 Cannabinoid Receptor Inverse Agonists/Antagonists

Obesity and metabolic syndrome, along with drug dependence (nicotine, alcohol, opiates), are two of the major therapeutic applications for CB1 cannabinoid receptor antagonists and inverse agonists. In the present study, we report the synthesis and structure−affinity relationships of 1,5-diphenylimidazolidine-2,4-dione and 1,3,5-triphenylimidazolidine-2,4-dione derivatives. These new 1,3,5-triphenylimidazolidine-2,4-dione derivatives and their thio isosteres were obtained by an original pathway and exhibited interesting affinity and selectivity for the human CB1 cannabinoid receptor. A [35S]-GTPγS binding assay revealed the inverse agonist properties of the compounds at the CB1 cannabinoid receptor. Furthermore, molecular modeling studies were conducted in order to delineate the binding mode of this series of derivatives into the CB1 cannabinoid receptor. 1,3-Bis(4-bromophenyl)-5-phenylimidazolidine-2,4-dione (25) and 1,3-bis(4-chlorophenyl)-5-phenylimidazolidine-2,4-dione (23) are the imidazolidine-2,4-dione derivatives possessing the highest affinity for the human CB1 cannabinoid receptor reported to date.