Characterization of functional effects of Z-338, a novel gastroprokinetic agent, on the muscarinic M1, M2, and M3 receptors expressed in Xenopus oocytes.
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 M1, M2, and M3 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 M1, M3 receptors or muscarinic M2 receptors/G protein-gated inward rectifying K+ channels (Kir3.1 channels). In oocytes expressing muscarinic M1 receptors, Z-338 inhibited the acetylcholine-induced Ca2+ -activated Cl- current with an IC50 of 1.8 microM. In oocytes expressing muscarinic M2 receptors/Kir3.1 channels, Z-338 inhibited the acetylcholine-induced K+ currents with an IC50 of 10.1 microM, whereas in oocytes expressing muscarinic M3 receptors, Z-338 did not inhibit the acetylcholine-induced Ca2+ -activated Cl- current in a concentration-dependent manner. These results indicate that Z-338 is a potent antagonist not for muscarinic M3 receptor but for both muscarinic M1 and M2 receptors. Thus, Z-338 is a gastrokinetic agent with a unique profile.
Doi
Y
Y
Department of Pharmacology Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
Murasaki
O
O
Kaibara
M
M
Uezono
Y
Y
Hayashi
H
H
Yano
K
K
Taniyama
K
K
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005765:Gastrointestinal Agents / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D043643:Receptor, Muscarinic M1 / Q000235:genetics / Q000502:physiology; D043585:Receptor, Muscarinic M2 / Q000235:genetics / Q000502:physiology; D043587:Receptor, Muscarinic M3 / Q000235:genetics / Q000502:physiology; D011976:Receptors, Muscarinic / Q000235:genetics / Q000502:physiology*; D015203:Reproducibility of Results; D013844:Thiazoles / Q000494:pharmacology*; D014981:Xenopus
D001549:Benzamides; D005765:Gastrointestinal Agents; D018727:Muscarinic Antagonists; D010880:Piperidines; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; D013844:Thiazoles; D010890:Pirenzepine; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium; C410959:Z 338; D000109:Acetylcholine; C048593:otenzepad; D011188:Potassium