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

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