Cannabinoid receptor allosteric sites

Cannabinoid receptor allosteric sites are distinct binding regions on the CB1 and CB2 G protein-coupled receptors that are topographically separate from the orthosteric site where endogenous cannabinoids like anandamide bind [1, 3]. These sites serve as targets for allosteric modulators, which fine-tune receptor activity by altering the affinity or efficacy of orthosteric ligands without necessarily activating the receptor independently [2, 7]. Positive allosteric modulators (PAMs) enhance signaling and are being explored for treating chronic pain and neurodegeneration, while negative allosteric modulators (NAMs) reduce signaling and show potential for managing obesity and addiction [11, 15]. By modulating rather than fully activating or blocking the receptor, these sites offer a therapeutic window to achieve clinical benefits while minimizing the psychoactive or psychiatric side effects associated with traditional orthosteric drugs [6, 10]. Recent structural studies have identified specific pockets within the transmembrane domains and extrahelical regions that facilitate these interactions, providing a basis for the design of highly selective ligands [5, 8].

Other names

CB1 allosteric siteCB2 allosteric siteCannabinoid receptor exositesNon-orthosteric cannabinoid binding sitesCBR allosteric sites

Drugs targeting these sites act as positive allosteric modulators (PAMs), negative allosteric modulators (NAMs), or ago-allosteric modulators to fine-tune the affinity and efficacy of orthosteric ligands at the CB1 and CB2 receptors.