The Molecular Basis of Cannabinoid Activity: Application to Therapeutics Design and Discovery for Cannabis Use Disorders

Abstract

The endocannabinoid signaling system is a ubiquitous means of (sub) cellular information transduction. Investigation of the system’s molecular components and the biochemical processes they participate in was stimulated some 25 years ago by seminal evidence that Δ9-tetrahydrocannabinol (Δ9-THC), the principal psychoactive component of Cannabis sp., exerts its psychotropic effects mainly through engaging and activating a class-A (rhodopsin-like) G protein-coupled receptor (GPCR), cannabinoid receptor 1 (CB1R), in the central nervous system. Subsequent investigations have explored the mechanisms of action of other phytocannabinoids (e.g., cannabidiol) and the principal endogenous cannabinoid lipid transmitters in humans and other mammals [the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG)], leading to the identification of an additional cannabinoid receptor [cannabinoid receptor 2 (CB2R)] and insight into the key physiological roles of the enzymes monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH) in terminating, respectively, 2-AG and AEA signaling functions. The importance of the endocannabinoid system in regulating many biological processes has stimulated the design and synthesis of structurally diverse small molecules as candidate therapeutics targeted to CB1R, CB2R, MGL, or FAAH. Given the increasing prevalence of legalized social and medicinal cannabis use and the emergence of ultra-potent, synthetic cannabinoids as illicit “street drugs,” current medicinal chemistry efforts aim to address the public health problems presented by cannabis use disorders (CUDs), both acute (e.g., cannabis overdose) and chronic (i.e., addiction). Within this context, this review discusses various therapeutic modalities targeted to CB1R, CB2R, MGL, and FAAH and highlights their potential to yield CUD therapies. Intrinsic pharmacological properties of CB1R neutral antagonists and MGL and FAAH inhibitors are regarded as key to potentially safe and efficacious medications for treating acute cannabis toxicity and/or CUDs.