In vitro and mouse in vivo characterization of the potent free fatty acid 1 receptor agonist TUG-469

• Published in: Naunyn-Schmiedeberg's archives of pharmacology 2013-12, Vol.386 (12), p.1021-1030
• Main Authors: Urban, C., Hamacher, A., Partke, H. J., Roden, M., Schinner, S., Christiansen, E., Due-Hansen, M. E., Ulven, T., Gohlke, H., Kassack, M. U.
• Format: Article
• Language: English
• Subjects: Aniline Compounds - pharmacology; Animals; Biomarkers - blood; Biomedical and Life Sciences; Biomedicine; Blood Glucose - drug effects; Blood Glucose - metabolism; Calcium Signaling - drug effects; Cell Line, Tumor; Cyclic AMP - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Hypoglycemic Agents - pharmacology; Insulin - blood; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Male; Methylamines - pharmacology; Mice; Mice, Obese; Neurosciences; Original Article; Pharmacology/Toxicology; Phenylpropionates - pharmacology; Prediabetic State - blood; Prediabetic State - diagnosis; Prediabetic State - drug therapy; Propionates - pharmacology; Rats; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Recombinant Proteins - metabolism; Time Factors; Transfection
• ISSN: 0028-1298; 1432-1912
• DOI: 10.1007/s00210-013-0899-3

Activation of the G protein-coupled free fatty acid receptor 1 (FFA1; formerly known as GPR40) leads to an enhancement of glucose-stimulated insulin secretion from pancreatic β-cells. TUG-469 has previously been reported as a potent FFA1 agonist. This study was performed to confirm the higher in vitro potency of TUG-469 compared to the reference FFA1 agonist GW9508 and to prove in vivo activity in a pre-diabetic mouse model. The in vitro pharmacology of TUG-469 was studied using Ca 2+ -, cAMP-, and impedance-based assays at recombinant FFA1 and free fatty acid receptor 4, formerly known as GPR120 (FFA4) expressing 1321N1 cells and the rat insulinoma cell line INS-1. Furthermore, we investigated the systemic effect of TUG-469 on glucose tolerance in pre-diabetic New Zealand obese (NZO) mice performing a glucose tolerance test after intraperitoneal administration of 5 mg/kg TUG-469. In comparison to GW9508, TUG-469 showed a 1.7- to 3.0-times higher potency in vitro at 1321N1 cells recombinantly expressing FFA1. Both compounds increased insulin secretion from rat insulinoma INS-1 cells. TUG-469 is > 200-fold selective for FFA1 over FFA4. Finally, a single dose of 5 mg/kg TUG-469 significantly improved glucose tolerance in pre-diabetic NZO mice. TUG-469 turned out as a promising candidate for further drug development of FFA1 agonists for treatment of type 2 diabetes mellitus.