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 targeting the endocannabinoid system. Axially chiral cannabinols (axCBNs) are unnatural cannabinols (CBNs) that bear an additional C10 substituent, which twists the cannabinol biaryl framework out of planarity creating an axis of chirality. This unique structural modification is hypothesized to enhance both the physical and biological properties of cannabinoid ligands, thus ushering in the next generation of endocannabinoid system chemical probes and cannabinoid-inspired leads for drug development. 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) atropisomerism, 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 endocannabinoid system.

Therapeutic Potential of Minor Cannabinoids in Dermatological Diseases—A Synthetic Review

“…The Friedel–Crafts method relies on electrophilic aromatic substitution reactions, where desired cannabinoids are formed through the reaction of aromatic compounds with electrophiles. All these methods require quality control, analysis, and specialized knowledge to ensure the purity and compliance of the obtained cannabinoids with specific standards [ 7 , 8 , 9 ].…”

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 . Nonetheless, this study demonstrates the value of collaboration and the importance of finding new molecular scaffolds 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

“…Abnormal CBD 4 is a CBD regioisomer in which the terpene subunit is positioned ortho to the n -pentyl substituent ( vs the para relationship present in “normal” CBD 1 ), a structural difference for binding to other targets in future analogues. Further structure–activity relationship (SAR) studies show that the substitution of the alkyl chain from Abn-CBD, the relative position of aromatic groups, and sites with the ability to form hydrogen bonds are important for binding to GPR18 and GPR55. , These findings suggest that synthetic investigations toward unnatural cannabinoid derivatives, herein referred to as “neocannabinoids”, including abnormal H 2 CBD 6 , can greatly benefit therapeutic applications. − …”