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

Yohimbine, a potent alpha2A-adrenergic receptor (α2AAR) antagonist, was found to carry therapeutic potential for type 2 diabetes through improving insulin release. However, adverse side effects mediated by its actions in the brain hampered its use. Here, we have developed a novel peripherally acting α2AAR antagonist, CDS479-2, based on molecular docking analysis and modification of yohimbine's structure. The inactive-state structures of α2AAR, either bound to yohimbine, or bound to CDS479-2, were elucidated via cryo-electron microscopy method. Importantly, CDS479-2 has similar α2AAR antagonist activity as yohimbine, but with very limited access to the brain and thus protecting against the unwanted central effects, such as hypertension and anxiety. Moreover, single dose of CDS479-2 by injection or gavage showed potent glucose-lowering effects in a high-fat diet-induced obesity (DIO) mouse model for human type 2 diabetes. Remarkably, DIO mice having received 2 weeks of daily treatment of CDS479-2, exhibited sustained normoglycaemia, and increased density of insulin-producing beta cells, in which important proliferation related genes were found upregulated. Moreover, the overall protein expression levels of their pancreas were more similar to those of healthy control mice. Thus, CDS479-2 may indicate a new direction for type 2 diabetes treatment. The strategy we employed here may inspire the optimization of other drugs which have both peripheral and central targets.