GRK-biased adrenergic agonists for the treatment of type 2 diabetes and obesity

Abstract

Biased agonism of G protein-coupled receptors (GPCRs) offers potential for safer medications. Current efforts have explored the balance between G proteins and β-arrestin; however, other transducers like GPCR kinases (GRKs) remain understudied. GRK2 is essential for β 2 adrenergic receptor (β 2 AR)-mediated glucose uptake, but β 2 AR agonists are considered poor clinical candidates for glycemic management due to G s /cyclic AMP (cAMP)-induced cardiac side effects and β-arrestin-dependent desensitization. Using ligand-based virtual screening and chemical evolution, we developed pathway-selective agonists of β 2 AR that prefer GRK coupling. These compounds perform well in preclinical models of hyperglycemia and obesity and demonstrate a lower potential for cardiac and muscular side effects compared with standard β 2 -receptor agonists and incretin mimetics, respectively. Furthermore, the lead candidate showed favorable pharmacokinetics and was well tolerated in a placebo-controlled clinical trial. GRK-biased β 2 AR partial agonists are thus promising oral alternatives to injectable incretin mimetics used in the treatment of type 2 diabetes and obesity.