Characterization of Novel and Known Activators of Cannabinoid Receptor Subtype 2 Reveals Mixed Pharmacology That Differentiates Mycophenolate Mofetil and GW-842,166X from MDA7
Authors
International journal of molecular sciences. 2025 05 21; 26(10).
Abstract
CB and CB cannabinoid receptors are members of the GPCR superfamily that modulate the effects of endocannabinoids. CB is the most abundant CB receptor in the central nervous system, while CB is present both peripherally and in the brain. CB plays a role in inflammation, as well as neurodegenerative and psychiatric disorders. To identify new ligands for CB, we screened a library of FDA-approved drugs for activity at the receptor using a thallium flux assay, resulting in the discovery of the immunosuppressant mycophenolate mofetil as a potent, selective activator of CB. Further characterization of the compound confirmed agonist activity in a variety of complementary assays, including PI hydrolysis, cAMP inhibition, and β-arrestin recruitment. Radioligand binding assays established a non-competitive interaction with the site occupied by [H]CP55,940. CB agonists GW-842,166X and MDA7 were also profiled, revealing that GW-842,166X exhibits a similar activity profile to mycophenolate mofetil, whereas MDA7 presents a distinct profile. These differences provide insight into the complex CB pharmacology impacting preclinical and clinical studies, and ultimately, new treatment strategies for brain disorders.