Characterization of functional effects of Z-338, a novel gastroprokinetic agent, on the muscarinic M(1), M(2), and M(3) receptors expressed in Xenopus oocytes.

摘要

This study characterized the functional effects of a novel gastroprokinetic agent, N-[2-(diisopropylamino)ethyl]-2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1, 3-thiazole-4-carboxyamide monohydrochloride trihydrate (Z338), on the muscarinic M(1), M(2), and M(3) receptors expressed in Xenopus oocytes using the two-electrode voltage clamp method. Z-338 did not produce by itself any currents in oocytes expressing muscarinic M(1), M(3) receptors or muscarinic M(2) receptors/G protein-gated inward rectifying K(+) channels (Kir3.1 channels). In oocytes expressing muscarinic M(1) receptors, Z-338 inhibited the acetylcholine-induced Ca(2+)-activated Cl(-) current with an IC(50) of 1.8 muM. In oocytes expressing muscarinic M(2) receptors/Kir3.1 channels, Z-338 inhibited the acetylcholine-induced K(+) currents with an IC(50) of 10.1 muM, whereas in oocytes expressing muscarinic M(3) receptors, Z-338 did not inhibit the acetylcholine-induced Ca(2+)-activated Cl(-) current in a concentration-dependent manner. These results indicate that Z-338 is a potent antagonist not for muscarinic M(3) receptor but for both muscarinic M(1) and M(2) receptors. Thus, Z-338 is a gastrokinetic agent with a unique profile.