Development of a novel peripherally acting alpha2A- adrenergic receptor antagonist for anti-diabetic

Yohimbine, a potent α2AAR antagonist, has shown therapeutic potential for T2D by improving insulin release, but its clinical application has been limited by central nervous system (CNS) side effects. In this study, we developed a novel, peripherally acting α2AAR antagonist (CDS479-2) using molecular docking analysis and a bioisosteric replacement strategy applied to yohimbine`s structure. cryo-EM structures of α2AAR bound to either yohimbine or CDS479-2 confirm the molecular basis of α2AAR antagonism, validate our docking models, and reveal key ligand-receptor interactions for future drug design.

Importantly, animal studies demonstrated that acute administration of CDS479-2 effectively lowered blood glucose and improved glucose tolerance in diabetic mice, without central side effects such as anxiety or blood pressure elevation commonly associated with α2AAR antagonism. Remarkably, once-daily administration of CDS479-2 for 2 weeks resulted in sustained normoglycemia and increased pancreatic β-cell density in diet-induced obese (DIO) mice, with upregulation of key genes involved in β-cell maturation and proliferation.