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

Abstract

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.

Teaching an Old Dog New Tricks for Achieving CB2-Selective Inverse Agonism

“…It remains to be seen whether the ultimate comment in the manuscript will be realized, whether "the strategy and experimental framework disclosed herein may aid in the structure-based design of agonists, antagonists, and inverse agonists for GPCRs beyond CB 2 R." There are many different types of toggle switch amino acid sequences� CWxP here, while others include NPxxY, D/ERY, etc.�and influencing remote switches directly by ligands can also be a challenge. 9 Nonetheless, this study demonstrates the value of collaboration and the importance of finding new molecular scaffolds 10 for further probing and understanding the complex endocannabinoid system. Without a doubt, switching off the CB 2 R function will switch on creative science muscles around the world, encouraging more collaborative teams to assemble to achieve endocannabinoid system understanding and drug discovery.…”

Synthesis of Neocannabinoids Using Controlled Friedel-Crafts Reactions

“…Experimental procedures, analytical data, 1 H and 13 C NMR spectra of all newly synthesized compounds, and DFT calculation details (PDF).…”

“…9,10 These findings suggest that synthetic investigations towards new, unnatural cannabinoid derivatives and isomers (herein referred to as "neocannabinoids") including abnormal H2CBD 6 can greatly benefit therapeutic applications. 11,12,13 A number of routes for the chemical synthesis of CBD and related molecules have been devised (Scheme 1). [14][15][16][17] The most efficient approach leverages Friedel-Crafts alkylation of olivetol 7 and chiral allylic alcohols such as menthadienol 8 under mild acidic conditions affording CBD through an SN1' mechanism.…”