Discovery of Dimethyl Shikonin Oxime 5a, a Potent, Selective Bombesin Receptor Subtype-3 Agonist for the Treatment of Type 2 Diabetes Mellitus.

Bombesin receptor subtype-3 (BB 3 , BRS-3) is an orphan G αq protein-coupled receptor. The characterization of novel synthetic ligands for BB 3 is an alternative and attractive strategy to study its diverse physiological functions. Here, we uncovered the intimate pairing of DMAKO-00 and its derivatives with BB 3 . Dimethyl shikonin oxime 5a (DSO-5a) was identified as the most potent agonist for BB 3 (pEC 50 = 8.422 in IP-1 accumulation), which was 898-fold more potent than DMAKO-00. Importantly, without brain penetration, DSO-5a improved glucose tolerance in C57BL/6 mice through BB 3 and ameliorated glucose homeostasis in diabetic db/db mice. We further revealed that DSO-5a upregulated PPAR-gamma activity via BB 3 through a quantitative proteomics approach. Collectively, our study demonstrated that DSO-5a, a representative compound of DMAKO-00 derivatives, is a potent, selective, and low-brain-penetrating agonist for BB 3 , and BB 3 is a promising treatment target for type 2 diabetes mellitus.