Axially Chiral Cannabinoids: Design, Synthesis, and Cannabinoid Receptor Affinity

The resorcinol-terpene phytocannabinoid template is a privileged scaffold for the development of diverse therapeutics target-ing the endocannabinoid system. Axially chiral cannabinols (axCBNs) are unnatural cannabinols (CBNs) that bear an addi-tional C10 substituent, which twists the cannabinol biaryl framework out of planarity creating an axis of chirality. This “es-cape from flatland” is hypothesized to enhance both the physical and biological properties of cannabinoid ligands, thus ush-ering in the next generation of endocannabinoid system chemical probes and cannabinoid-inspired leads for drug develop-ment. In this full report, we describe the philosophy guiding the design of axCBNs as well as several synthetic strategies for their construction. We also introduce a second class of axially chiral cannabinoids inspired by cannabidiol (CBD), termed axially chiral cannabidiols (axCBDs). Finally, we provide an analysis of axially chiral cannabinoid (axCannabinoid) atro-pisomerism, which spans two classes (class 1 and 3 atropisomers), and provide first evidence that axCannabinoids retain—and in some cases, strengthen—affinity and functional activity at cannabinoid receptors. Together, these findings present a promising new direction for the design of novel cannabinoid ligands for drug discovery and exploration of the complex en-docannabinoid system.