Abstract
Cannabidiol (CBD), a bicyclic non-psychoactive cannabinoid biosynthesized by Cannabis spp. of plants, has attracted significant interest in the past decade due to its therapeutic properties. In 2018, the US FDA approved Epidiolex®, a CBD–based drug for the treatment of two rare epileptic seizure disorders.
CBD possesses two chiral centers at C3 and C4 on its terpenoid moiety and exhibits cis–trans stereoisomerism along the C3–C4 bond axis. (−)–trans–(3R,4R)–CBD, the natural CBD, is biosynthesized by the cannabis plant, while the unnatural (+)–trans–(3S,4S)–CBD is obtained via chemical synthesis. Both trans isomers exhibit broad in vitro and in vivo biological activities; typically, the unnatural stereoisomer (+)–trans-CBD and its derivatives exhibited more potent activities in comparison to the corresponding (−)–trans isomers. On the other hand, cis–CBD isomers have only been reported recently and can undergo epimerization into trans isomers.
There is a significant opportunity to explore unique synthetic methods and biological activities of stereoisomers of CBD that may pave the path for the development of novel therapeutics. Herein, as a novel direction in cannabinoids, we review the chemistry of CBD stereoisomers, their structure–activity relationships, target selectivity and efficacy in animal models.