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Seven-transmembrane receptors signal via G-protein- and β-arrestin-dependent pathways. We describe a peripheral CB 1 R antagonist (MRI-1891) highly biased toward inhibiting CB 1 R-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 CB 1 R occupancy. By contrast, the unbiased global CB 1 R 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, CB 1 R activation suppresses insulin-induced akt-2 phosphorylation, preventable by MRI-1891, βArr2 knockdown or overexpression of CB 1 R-interacting protein. MRI-1891, but not rimonabant, interacts with nonpolar residues on the N-terminal loop, including F108, and on transmembrane helix-1, including S123, a combination that facilitates βArr2 bias. Thus, CB 1 R promotes muscle insulin resistance via βArr2 signaling, selectively mitigated by a biased CB 1 R antagonist at reduced risk of central nervous system (CNS) side effects.

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

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