Axially Chiral Cannabinols: A New Platform for Cannabinoid‐Inspired Drug Discovery

Abstract

Phytocannabinoids (and synthetic analogs thereof) are gaining significant attention as promising leads in modern medicine. Considering this, new directions for the design of phytocannabinoid‐inspired molecules is of immediate interest. In this regard, we have hypothesized that axially‐chiral‐cannabinols (ax‐CBNs), unnatural and unknown isomers of cannabinol (CBN) may be valuable scaffolds for cannabinoid‐inspired drug discovery. There are two main factors directing our interest to these scaffolds: (a) ax‐CBNs would have ground‐state three‐dimensionality; ligand‐receptor interactions can be more significant with complimentary 3D‐topology, and (b) ax‐CBNs at their core structure are biaryl molecules, generally attractive platforms for pharmaceutical development due to their ease of functionalization and stability. Herein we report a synthesis of ax‐CBNs, examine physical properties experimentally and computationally, and perform a comparative analysis of ax‐CBN and THC in mice behavioral studies.

A nonneglectable stereochemical factor in drug development: Atropisomerism

“…With the development of chiral research techniques, atropisomerism has attracted increasing attention in recent years and has been a crucial stereochemical factor in drug development. 96,97 Many bioactive compounds exhibit atropisomerism in pharmaceutical chemistry, and their atropisomers usually display different biological properties. This review summarizes some examples of atropisomers encountered in drug research and their pharmacological, pharmacokinetic, and toxic properties.…”

Controlling Ibrutinib’s Conformations about Its Heterobiaryl Axis to Increase BTK Selectivity

“…This led to the hypothesis that preorganizing the CEPs of promiscuous unstable atropisomeric or pro-atropisomeric axes toward the preferred conformations of a target would allow for the “programming” of the scaffold’s selectivity toward that target. Beyond our work, there have been several recent examples of conformational control about a prospective atropisomeric axis to modulate the properties of biologically active small molecules, including Boehringer Ingelheim’s mutant EGFR inhibitors, Lorlatinib, and Grenning’s cannabinol derivatives . More recently, a team at Janssen has disclosed an atropisomeric BTK inhibitor where the configuration of the atropisomeric axis was crucial for activity. , …”

“…Beyond our work, there have been several recent examples of conformational control about a prospective atropisomeric axis to modulate the properties of biologically active small molecules, including Boehringer Ingelheim's mutant EGFR inhibitors, 25 Lorlatinib, 26 and Grenning's cannabinol derivatives. 27 More recently, a team at Janssen has disclosed an atropisomeric BTK inhibitor where the configuration of the atropisomeric axis was crucial for activity. 28,29 Herein we describe studies where we evaluated analogues of ibrutinib where the CEP of the 3-aryl−aryl axis is shifted to more orthogonal conformations by the addition of methyl groups adjacent to this axis.…”

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

“…23 Recently, we proposed that axially chiral analogs of cannabinoids may serve as valuable tools and leads for cannabinoid-based drug discovery (axCannabinoids, Figure 1C). 24 Scaffolds of this type are attractive for the following reasons: (i.) axCannabinoids are three-dimensional ligands (due to axial chirality rather than the trans-point chirality of trans-THCs).…”