title: Synthesis, biological evaluation, and structural studies on N1 and C5 substituted cycloalkyl analogues of the pyrazole class of CB1 and CB2 ligands.
abstract: A series of N1 and C5 substituted cycloalkyl and C5 4-methylphenyl analogues of the N-(piperidin-1-yl)-4-methyl-1H-pyrazole-3-carboxamide class of cannabinoid ligands were synthesized. The analogues were evaluated for CB1 and CB2 receptor binding affinities and receptor subtype selectivity. The effects of pyrazole substitution on ligand conformation and as such receptor affinities was not readily apparent; therefore, the geometries of the N1 and C5 substituents relative to the pyrazole ring were studied using high field NMR spectroscopy and systematic molecular mechanics geometry searches. An analysis of the relative ring geometries and functional group orientations provides new insight into the structural requirements of the CB1 and CB2 ligand binding pocket.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee-Memphis, 847 Monroe Avenue, Memphis, TN 38103, USA.
authors.forename: Mathangi
authors.initials: M
authors.lastname: Krishnamurthy
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Bob M
authors.initials: BM
authors.lastname: Moore
mesh_terms: D000818:Animals; D001671:Biochemistry / Q000379:methods; D016466:CHO Cells; D006224:Cricetinae; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry* / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C103505:AM 251; C031280:pyrazole