Bow Eric W, Rimoldi John M
Department of BioMolecular Sciences, Division of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, MS, USA.
Perspect Medicin Chem. 2016 Jun 28;8:17-39. doi: 10.4137/PMC.S32171. eCollection 2016.
The cannabinoids are members of a deceptively simple class of terpenophenolic secondary metabolites isolated from Cannabis sativa highlighted by (-)-Δ(9)-tetrahydrocannabinol (THC), eliciting distinct pharmacological effects mediated largely by cannabinoid receptor (CB1 or CB2) signaling. Since the initial discovery of THC and related cannabinoids, synthetic and semisynthetic classical cannabinoid analogs have been evaluated to help define receptor binding modes and structure-CB1/CB2 functional activity relationships. This perspective will examine the classical cannabinoids, with particular emphasis on the structure-activity relationship of five regions: C3 side chain, phenolic hydroxyl, aromatic A-ring, pyran B-ring, and cyclohexenyl C-ring. Cumulative structure-activity relationship studies to date have helped define the critical structural elements required for potency and selectivity toward CB1 and CB2 and, more importantly, ushered the discovery and development of contemporary nonclassical cannabinoid modulators with enhanced physicochemical and pharmacological profiles.
大麻素是从大麻中分离出的一类看似简单的萜酚类次生代谢产物，以（-）-Δ（9）-四氢大麻酚（THC）为代表，其引发的独特药理作用主要由大麻素受体（CB1或CB2）信号传导介导。自最初发现THC和相关大麻素以来，已对合成和半合成的经典大麻素类似物进行了评估，以帮助确定受体结合模式以及结构与CB1/CB2功能活性之间的关系。本观点将审视经典大麻素，特别强调五个区域的构效关系：C3侧链、酚羟基、芳香A环、吡喃B环和环己烯基C环。迄今为止，累积的构效关系研究有助于确定对CB1和CB2具有效力和选择性所需的关键结构要素，更重要的是，推动了具有增强理化和药理特性的当代非经典大麻素调节剂的发现和开发。
