Krishnamurthy Mathangi, Li Wei, Moore Bob M
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee-Memphis, 847 Monroe Avenue, Memphis, TN 38103, USA.
Bioorg Med Chem. 2004 Jan 15;12(2):393-404. doi: 10.1016/j.bmc.2003.10.045.
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.
合成了一系列N-（哌啶-1-基）-4-甲基-1H-吡唑-3-甲酰胺类大麻素配体的N1和C5取代的环烷基以及C5 4-甲基苯基类似物。对这些类似物进行了CB1和CB2受体结合亲和力以及受体亚型选择性的评估。吡唑取代对配体构象以及受体亲和力的影响并不明显；因此，使用高场核磁共振光谱和系统的分子力学几何结构搜索研究了N1和C5取代基相对于吡唑环的几何结构。对相对环几何结构和官能团取向的分析为CB1和CB2配体结合口袋的结构要求提供了新的见解。
