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

Bombesinreceptor subtype-3 (BB3, BRS-3) isan orphanG(alpha q) protein-coupled receptor. The characterizationof novel synthetic ligands for BB3 is an alternative andattractive strategy to study its diverse physiological functions.Here, we uncovered the intimate pairing of DMAKO-00 and its derivativeswith BB3. Dimethyl shikonin oxime 5a (DSO-5a) was identifiedas the most potent agonist for BB3 (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 tolerancein C57BL/6 mice through BB3 and ameliorated glucose homeostasisin diabetic db/db mice. We further revealed that DSO-5a upregulatedPPAR-gamma activity via BB3 through a quantitative proteomicsapproach. Collectively, our study demonstrated that DSO-5a, a representativecompound of DMAKO-00 derivatives, is a potent, selective, and low-brain-penetratingagonist for BB3, and BB3 is a promising treatmenttarget for type 2 diabetes mellitus.

Automated summary

The study discovered the close association between DMAKO-00 and its derivatives with BB3, with DSO-5a identified as the most potent agonist for BB3. DSO-5a improved glucose tolerance in C57BL/6 mice and glucose homeostasis in diabetic db/db mice through BB3. It was further revealed that DSO-5a upregulated PPAR-γ activity via BB3 through quantitative proteomics. Overall, the study demonstrated that DSO-5a is a potent, selective, and low-brain-penetrating agonist for BB3, and BB3 is a promising treatment target for type 2 diabetes mellitus.