Functional Selectivity of a Biased Cannabinoid-1 Receptor (CB₁R) Antagonist.

ABSTRACT: Seven-transmembrane receptors signal via G-protein- and β-arrestin-dependent pathways. We describe a peripheral CB₁R antagonist (MRI-1891) highly biased toward inhibiting CB₁R-induced β-arrestin-2 (βArr2) recruitment over G-protein activation. In obese wild-type and βArr2-knockout (KO) mice, MRI-1891 treatment reduces food intake and body weight without eliciting anxiety even at a high dose causing partial brain CB₁R occupancy. By contrast, the unbiased global CB₁R antagonist rimonabant elicits anxiety in both strains, indicating no βArr2 involvement. Interestingly, obesity-induced muscle insulin resistance is improved by MRI-1891 in wild-type but not in βArr2-KO mice. In C2C12 myoblasts, CB₁R activation suppresses insulin-induced akt-

SUBMITTER: Liu Z 

PROVIDER: S-EPMC8204328 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature