Functional Selectivity Of A Biased Cannabinoid-1 Receptor (Cb1r) Antagonist

Seven-transmembrane receptors signal via G-protein- and beta-arrestindependent pathways. We describe a peripheral CB,R antagonist (MRI-1891) highly biased toward inhibiting CB,R-induced beta-arrestin-2 (beta Arr2) recruitment over G-protein activation. In obese wild-type and beta Arr2-knockout (1(0) 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 beta Arr2 involvement. Interestingly, obesity-induced muscle insulin resistance is improved by MRI-1891 in wild-type but not in beta Arr2-KO mice. In C2C12 myoblasts, CB1R activation suppresses insulin-induced akt-2 phosphorylation, preventable by MRI-1891, beta Arr2 knockdown or overexpression of CB1R-interacting protein. MRI-1891, but not rimonabant, interacts with nonpolar residues on the N-terminal loop, including F108, and on transmembrane helix-1, including 5123, a combination that facilitates beta Arr2 bias. Thus, CB1R promotes muscle insulin resistance via beta Arr2 signaling, selectively mitigated by a biased CB1R antagonist at reduced risk of central nervous system (CNS) side effects.