Determination of the Cannabinoid CB1 Receptor's Positive Allosteric Modulator Binding Site through Mutagenesis Studies.

ABSTRACT: Positive allosteric modulators (PAMs) of the cannabinoid CB1 receptor (CB₁) offer potential therapeutic advantages in the treatment of neuropathic pain and addiction by avoiding the adverse effects associated with orthosteric CB₁ activation. Here, molecular modeling and mutagenesis were used to identify residues central to PAM activity at CB₁. Six putative allosteric binding sites were identified in silico, including novel sites previously associated with cholesterol binding, and key residues within each site were mutated to alanine. The recently determined ZCZ011 binding site was found to be essential for allosteric agonism, as GAT228, GAT229 and ZCZ011 all increased wild-type G protein dissociation in the absence of an orthosteric ligand; activity that wa

SUBMITTER: Green HM 

PROVIDER: S-EPMC10892375 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature