Discovery of Dimethyl Shikonin Oxime 5a, a Potent, Selective Bombesin Receptor Subtype-3 Agonist for the Treatment of Type 2 Diabetes Mellitus.
J Med Chem
; 66(12): 8011-8029, 2023 06 22.
Article
em En
| MEDLINE
| ID: mdl-37272653
ABSTRACT
Bombesin receptor subtype-3 (BB3, BRS-3) is an orphan Gαq protein-coupled receptor. The characterization of novel synthetic ligands for BB3 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 BB3. Dimethyl shikonin oxime 5a (DSO-5a) was identified as the most potent agonist for BB3 (pEC50 = 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 BB3 and ameliorated glucose homeostasis in diabetic db/db mice. We further revealed that DSO-5a upregulated PPAR-gamma activity via BB3 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 BB3, and BB3 is a promising treatment target for type 2 diabetes mellitus.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Receptores da Bombesina
/
Diabetes Mellitus Tipo 2
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article