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

  • ACS Pharmacol Transl Sci. 2021 Apr 8;4(3):1175-1187. doi: 10.1021/acsptsci.1c00048.
Ziyi Liu  1 ,  Malliga R Iyer  1 ,  Grzegorz Godlewski  1 ,  Tony Jourdan  1 ,  Jie Liu  1 ,  Nathan J Coffey  1 ,  Charles N Zawatsky  1 ,  Henry L Puhl  1 ,  Jürgen Wess  2 ,  Jaroslawna Meister  2 ,  Jeih-San Liow  3 ,  Robert B Innis  3 ,  Sergio A Hassan  4 ,  Yong Sok Lee  4 ,  George Kunos  1 ,  Resat Cinar  1
Affiliations
  • 1. Laboratory of Physiologic Studies and Section on Cellular Biophotonics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-9304, United States.
  • 2. Laboratory of Bioorganic Chemistry, National Institute on Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland 20892-0001, United States.
  • 3. Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland 20892-9663, United States.
  • 4. Bioinformatics and Computational Biosciences Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States.
PMID: 34151207 DOI: 10.1021/acsptsci.1c00048
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-2 phosphorylation, preventable by MRI-1891, βArr2 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 S123, a combination that facilitates βArr2 bias. Thus, CB1R promotes muscle Insulin resistance via βArr2 signaling, selectively mitigated by a biased CB1R antagonist at reduced risk of central nervous system (CNS) side effects.

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