Evidence for effective suppression of INa and IK(DR) by AS2034178 (bis{2-[(4-{(4′-(2-hydroxyethoxy)-2′-methyl[1,1′-biphenyl]-3-yl)methoxy}phenyl]methyl]-3,5-dioxo-1,2,4-oxadiazolidin-4-ide} tetrahydrate), an agonist of free fatty acid receptor

Abstract

<p>AS2034178, an agonist of free fatty acid receptor-1 or G protein-coupled receptor 40, enhances pancreatic β-cell function. Its impact on ionic currents in excitable cells, particularly pituitary tumor (GH3) cells, was investigated. AS2034178 suppressed transient (INa(T)) and late (INa(L)) components of voltage-gated Na⁺ current (INa) with IC50 values of 29.8 and 5.3 µM, respectively. It did not alter current–voltage relationship but shifted steady-state inactivation curve of INa(T) leftward. AS2034178 also blocked persistent Na⁺ current (INa(P)) activated by long-lasting ramp voltages, and subsequent application of deltamethrin or tefluthrin attenuated its suppression. The compound prolonged recovery of INa(P) inactivation, shifted its inactivation curve, and shortened time constant for IN(P) decay. Additionally, AS2034178 suppressed delayed-rectifier K⁺ current (IK(DR)) with a dissociation constant of 6.23 µM. Docking studies suggested AS2034178′s ability to interact with amino acid residues in hNaV1.7 channels.(supplementary data). AS2034178′s effects on ionic currents (INa and IK(DR)) contribute to its mechanisms of action in culture or in vivo.</p>