Synthesis and activity of 1,3,5-triphenylimidazolidine-2,4-diones and 1,3,5-triphenyl-2-thioxoimidazolidin-4-ones: Characterization of new CB 1 cannabinoid receptor inverse agonists/antagonists

Giulio G. Muccioli, Johan Wouters, Caroline Charlier, Gerhard K E Scriba, Teresa Pizza, Pierluigi Di Pace, Paolo De Martino, Wolfgang Poppitz, Jacques H. Poupaert, Didier M. Lambert

Research output: Contribution to journalArticle

Abstract

Obesity and metabolic syndrome, along with drug dependence (nicotine, alcohol, opiates), are two of the major therapeutic applications for CB 1 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.

Original languageEnglish
Pages (from-to)872-882
Number of pages11
JournalJournal of Medicinal Chemistry
Volume49
Issue number3
DOIs
Publication statusPublished - 9 Feb 2006

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  • Datasets

    CCDC 273358: Experimental Crystal Structure Determination

    Muccioli, G. (Contributor), WOUTERS, J. (Contributor), Charlier, C. (Contributor), Scriba, G. K. E. (Contributor), Pizza, T. (Contributor), Di Pace, P. (Contributor), De Martino, P. (Contributor), Poppitz, W. (Contributor), Poupaert, J. H. (Contributor) & Lambert, D. M. (Contributor), Cambridge Crystallographic Data Centre, 1 Jan 2007

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