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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Cannabinoid Receptor Agonists
Cannabinoid Receptor CB1
Cannabinoid Receptors
Derivatives
Opiate Alkaloids
Cannabinoid Receptor Antagonists
Molecular modeling
Nicotine
Substance-Related Disorders
Assays
Obesity
Alcohols
Pharmaceutical Preparations

Cite this

Muccioli, Giulio G. ; Wouters, Johan ; Charlier, Caroline ; Scriba, Gerhard K E ; Pizza, Teresa ; Di Pace, Pierluigi ; De Martino, Paolo ; Poppitz, Wolfgang ; Poupaert, Jacques H. ; Lambert, Didier M. / 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. In: Journal of Medicinal Chemistry. 2006 ; Vol. 49, No. 3. pp. 872-882.
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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.",
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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. / Muccioli, Giulio G.; Wouters, Johan; Charlier, Caroline; Scriba, Gerhard K E; Pizza, Teresa; Di Pace, Pierluigi; De Martino, Paolo; Poppitz, Wolfgang; Poupaert, Jacques H.; Lambert, Didier M.

In: Journal of Medicinal Chemistry, Vol. 49, No. 3, 09.02.2006, p. 872-882.

Research output: Contribution to journalArticle

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T1 - Synthesis and activity of 1,3,5-triphenylimidazolidine-2,4-diones and 1,3,5-triphenyl-2-thioxoimidazolidin-4-ones

T2 - Characterization of new CB 1 cannabinoid receptor inverse agonists/antagonists

AU - Muccioli, Giulio G.

AU - Wouters, Johan

AU - Charlier, Caroline

AU - Scriba, Gerhard K E

AU - Pizza, Teresa

AU - Di Pace, Pierluigi

AU - De Martino, Paolo

AU - Poppitz, Wolfgang

AU - Poupaert, Jacques H.

AU - Lambert, Didier M.

PY - 2006/2/9

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