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.

Figure 1.

(A) Major phytocannabinoids (THC, CBN, and CBD). (B) Representative synthetic cannabinoids. (C) Past efforts and this work: axCannabinoids as bioisosteric variants with improved physical and biological properties.

Figure 2.

axCBN retrosynthesis (A), forward synthesis (B), and representative synthetic shortcomings (C).

Figure 3.

Results from automated docking. axCBN-3 (green) docked within hCB₁R (gray) (A) and hCB₂R (cyan) (C), rac-axCBD-2 (orange) docked within hCB₁R (B) and hCB₂R (D). For docking scores, please see the text.

Figure 4.

Beyond cannabinoids: other “lead molecules” in principle can have atropisomeric counterparts with potentially improved pharmaceutical/therapeutic properties.

Scheme 1.

(A): Second-Generation Strategy Capable of Achieving C9 and C10 Disubstitution Is Challenged by a Competitive Propargyl Claisen Rearrangement. (B): Can the Innate [3,3] Reactivity Be Overturned in Favor of Dearomative [4+2] Cycloaddition?

Scheme 2.

Optimization (A), Scope (B), and Limitations (C) of Rh-Catalyzed Dearomative [4+2] Cycloaddition. (D) Synthesis of axCBN-2 and axCBN-3

Scheme 3.

(A) Observation of an E1_cb Elimination Reaction Yielding a Biaryl Reminiscent of Parent axCBD. (B) Cannabidiol (CBD) and Axially Chiral Cannabidiol (axCBD)

Scheme 4.

(A) Biaryl Synthesis via E1_cb Aromatization: Scalability and Scope Studies. (B) Synthesis of axCBD-1 and ax-CBD-2 Utilizing E1_cb Aromatization

Scheme 5.

(A) axCBNs Display “type 1” Atropisomerism. (B) axCBDs Display “type 3” Atropisomerism.

Scheme 6.

(A) axCannabinoid Summary. (B) Displacement of [³H]CP55940 Binding. (C) axCannabinoid Binding Affinity at Cannabinoid Receptors. (D) TRUPATH Gαi Activation

Scheme 7.

axCBN-3 Exhibits Two Distinct Affinities at hCB₁R (pKi_Hi = 9.4, pKi_Lo = 7.3), Unlike CBN (pKi = 6.2), Suggesting High Affinity Binding to the Active Conformation^{a a}Data are mean ± SEM of N = 3−4 experiments performed in triplicate.

Scheme 8.

Effect of Absolute Configuration on Affinity and Activity at Cannabinoid Receptors. (A) Preparation of Single Enantiomers. (B) Affinity Assays. (C) GTPγS. (D) TRUPATH Gαi1 Activation