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

doi:10.1021/jm050484f

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

Unite de recherche en chimie physique, theorique et structurale

Résultats de recherche: Contribution à un journal/une revue › Article › Revue par des pairs

Résumé

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.

langue originale	Anglais
Pages (de - à)	872-882
Nombre de pages	11
journal	Journal of Medicinal Chemistry
Volume	49
Numéro de publication	3
Les DOIs	https://doi.org/10.1021/jm050484f
Etat de la publication	Publié - 9 févr. 2006

SDG des Nations Unies

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10.1021/jm050484f

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CCDC 273358: Experimental Crystal Structure Determination
Muccioli, G. (Contributeur), Wouters, J. (Contributeur), Charlier, C. (Contributeur), Scriba, G. K. E. (Contributeur), Pizza, T. (Contributeur), Di Pace, P. (Contributeur), De Martino, P. (Contributeur), Poppitz, W. (Contributeur), Poupaert, J. H. (Contributeur) & Lambert, D. M. (Contributeur), Cambridge Crystallographic Data Centre, 1 janv. 2007
DOI: 10.5517/cc95g0x, http://www.ccdc.cam.ac.uk/services/structure_request?id=doi:10.5517/cc95g0x&sid=DataCite
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Muccioli, G. G., Wouters, J., Charlier, C., Scriba, G. K. E., Pizza, T., Di Pace, P., De Martino, P., Poppitz, W., Poupaert, J. H., & Lambert, D. M. (2006). 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. Journal of Medicinal Chemistry, 49(3), 872-882. https://doi.org/10.1021/jm050484f

@article{5c7adf5fcce141caa13de9d8d9e6190b,

title = "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",

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.",

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

year = "2006",

month = feb,

day = "9",

doi = "10.1021/jm050484f",

language = "English",

volume = "49",

pages = "872--882",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "3",

}

Muccioli, GG, Wouters, J, Charlier, C, Scriba, GKE, Pizza, T, Di Pace, P, De Martino, P, Poppitz, W, Poupaert, JH & Lambert, DM 2006, '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', Journal of Medicinal Chemistry, VOL. 49, Numéro 3, p. 872-882. https://doi.org/10.1021/jm050484f

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 et al.
Dans: Journal of Medicinal Chemistry, Vol 49, Numéro 3, 09.02.2006, p. 872-882.

Résultats de recherche: Contribution à un journal/une revue › Article › Revue par des pairs

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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

Y1 - 2006/2/9

N2 - 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.

AB - 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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