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3D-QSAR studies of arylpyrazole antagonists of cannabinoid receptor subtypes CB1 and CB2. A combined NMR and CoMFA approach.
J Med Chem. 2006 Jan 26; 49(2):625-36.JM

Abstract

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.

Authors+Show Affiliations

Department of Pharmaceutical & Pharmacological Sciences, College of Pharmacy, University of Houston, Texas 77204-5037, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16420048

Citation

Chen, Jian-Zhong, et al. "3D-QSAR Studies of Arylpyrazole Antagonists of Cannabinoid Receptor Subtypes CB1 and CB2. a Combined NMR and CoMFA Approach." Journal of Medicinal Chemistry, vol. 49, no. 2, 2006, pp. 625-36.
Chen JZ, Han XW, Liu Q, et al. 3D-QSAR studies of arylpyrazole antagonists of cannabinoid receptor subtypes CB1 and CB2. A combined NMR and CoMFA approach. J Med Chem. 2006;49(2):625-36.
Chen, J. Z., Han, X. W., Liu, Q., Makriyannis, A., Wang, J., & Xie, X. Q. (2006). 3D-QSAR studies of arylpyrazole antagonists of cannabinoid receptor subtypes CB1 and CB2. A combined NMR and CoMFA approach. Journal of Medicinal Chemistry, 49(2), 625-36.
Chen JZ, et al. 3D-QSAR Studies of Arylpyrazole Antagonists of Cannabinoid Receptor Subtypes CB1 and CB2. a Combined NMR and CoMFA Approach. J Med Chem. 2006 Jan 26;49(2):625-36. PubMed PMID: 16420048.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 3D-QSAR studies of arylpyrazole antagonists of cannabinoid receptor subtypes CB1 and CB2. A combined NMR and CoMFA approach. AU - Chen,Jian-Zhong, AU - Han,Xiu-Wen, AU - Liu,Qian, AU - Makriyannis,Alexandros, AU - Wang,Junmei, AU - Xie,Xiang-Qun, PY - 2006/1/20/pubmed PY - 2006/3/22/medline PY - 2006/1/20/entrez SP - 625 EP - 36 JF - Journal of medicinal chemistry JO - J Med Chem VL - 49 IS - 2 N2 - 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. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/16420048/3D_QSAR_studies_of_arylpyrazole_antagonists_of_cannabinoid_receptor_subtypes_CB1_and_CB2__A_combined_NMR_and_CoMFA_approach_ L2 - https://doi.org/10.1021/jm050655g DB - PRIME DP - Unbound Medicine ER -