3D-QSAR studies of arylpyrazole antagonists of cannabinoid receptor subtypes CB1 and CB2. A combined NMR and CoMFA approach

Jian Zhong Chen, Xiu Wen Han, Qian Liu, Alexandros Makriyannis, Junmei Wang, Xiang Qun Xie

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The present work focuses on the study of the three-dimensional (3D) structural requirements for selective antagonist activity of arylpyrazole compounds at the cannabinoid CB1 and CB2 receptors. Initially, a combined high-resolution two-dimensional (2D) NMR and computer modeling approach was carried out to study the solution structure of the key pyrazole derivative N-(piperidin-1-yl)-5-phenyl-1-(n-pentyl)-4-methyl-1H-pyrazole-3-carboxamide (AM263). By using the NMR-determined molecular conformers as templates, the 3D quantitative structure-activity relationship (QSAR) studies were performed with the comparative molecular field analysis (CoMFA) approach on a set of arylpyrazole cannabinoid receptor antagonists. Molecular alignments suitable for deriving valuable pharmacophoric features for this series of compounds were determined. Such systematic 3D-QSAR/CoMFA analyses of 29 molecules and their receptor affinities gave guidance for understanding the binding affinities of arylpyrazoles at the CB1 and CB2 binding sites, respectively, Comparison of CoMFA steric and potential contour maps for affinity at the two cannabinoid receptor subtypes helps to differentiate structural requirements for each subtype and serves as a basis for the design of later-generation analogues.

Original languageEnglish (US)
Pages (from-to)625-636
Number of pages12
JournalJournal of Medicinal Chemistry
Issue number2
Publication statusPublished - Jan 26 2006


ASJC Scopus subject areas

  • Organic Chemistry

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