GRK-biased adrenergic agonists for the treatment of type 2 diabetes and obesity.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 40555230.
- Also identified by DOI 10.1016/j.cell.2025.05.042.
- No licence information is recorded for this record.
- Because redistribution is not established, this page shows the abstract only. Follow the links below for the full text.
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<sub>2</sub> adrenergic receptor (β<sub>2</sub>AR)-mediated glucose uptake, but β<sub>2</sub>AR agonists are considered poor clinical candidates for glycemic management due to G<sub>s</sub>/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<sub>2</sub>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<sub>2</sub>-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<sub>2</sub>AR partial agonists are thus promising oral alternatives to injectable incretin mimetics used in the treatment of type 2 diabetes and obesity.
Medical subject headings
- Obesity
- Diabetes Mellitus, Type 2
- G-Protein-Coupled Receptor Kinase 2
- Adrenergic beta-2 Receptor Agonists
- Adrenergic Agonists