Chemistry Weekly Seminar-Robert Laprairie, Associate Professor

Title
Development of Novel Allosteric Modulators of the Cannabinoid Receptors

Abstract

The type 1 and type 2 cannabinoid receptors (CB1R and CB2R) participate in the regulation of numerous physiology functions and have been a major focus of pharmaceutical drug research since their identification and cloning. Over the past decade work from our lab and others has explored allosteric modulation of the cannabinoid receptors. Allosteric modulators act at distinct receptor sites from that of the endogenous ligand to augment (positive allosteric modulators [PAMs]) or diminish (negative allosteric modulators [NAMs]) endogenous ligand signaling. Allosteric modulation offers several potential advantages over ‘traditional’ orthosteric compounds that directly activate or inactivate a receptor such as an effect ceiling, greater receptor subtype selectivity, and reduced tolerance, dependence, or desensitization.

Our lab group has been characterizing both PAMs and NAMs. For our novel CB1R PAMs, we have been working closely with several other groups to improve the structure-activity relationship (SAR) of these compounds through iterative testing processes. Thus far, our group has found that this family of PAMs shows pre-clinical potential in rodent models of epilepsy. Meanwhile naturally occurring cannabinoids, including NAMs, may show efficacy in rodent models of substance use disorders.

Considering the strides made in allosteric pharmacology, many questions have arisen. Many NAMs of CB1R signaling display complex activity in vitro: increasing ligand binding but inhibiting signal transduction. CB1R PAMs and allosteric agonists may bind multiple receptor sites with unique effects on receptor conformation and signaling. Pre-clinical evidence exists to warrant the advancement of cannabinoid allosteric modulators as future medicines; however, a great deal of optimization must occur to advance these chemicals from lead compounds to true drugs.