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  • Title: Synthesis, cannabinoid receptor affinity, and molecular modeling studies of substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides.
    Author: Silvestri R, Cascio MG, La Regina G, Piscitelli F, Lavecchia A, Brizzi A, Pasquini S, Botta M, Novellino E, Di Marzo V, Corelli F.
    Journal: J Med Chem; 2008 Mar 27; 51(6):1560-76. PubMed ID: 18293908.
    Abstract:
    The new 1-phenyl-5-(1 H-pyrrol-1-yl)pyrazole-3-carboxamides were compared with the reference compounds AM251 and SR144528 for cannabinoid hCB 1 and hCB 2 receptor affinity. Compounds bearing 2,4-dichlorophenyl or 2,4-difluorophenyl groups at position 1 and 2,5-dimethylpyrrole moiety at position 5 of the pyrazole nucleus were generally more selective for hCB 1. On the other hand, the N-cyclohexyl group at the 3-carboxamide was the determinant for the hCB 2 selectivity, in particular when a 3,4-dichlorophenyl group was also present at position 1. Compound 26 was the most selective ligand for the hCB 1 receptor ( K i (CB 2)/ K i (CB 1) = 140.7). Derivative 30, the most potent hCB 1 ligand ( K i = 5.6 nM), was equipotent to AM251 and behaved as an inverse agonist in the cAMP assay (EC 50 approximately 1 nM). The carbonyl oxygen of both 26 and 30 formed a H-bond with K3.28(192), while the substituents at the nitrogen fitted in a pocket formed by lipophilic residues. This H-bonding interaction was proposed to account for the high affinity for receptors' inactive state and the inverse agonist activity.
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