Jpn. J. Pharmacol. 74 (2), 209-212 (1997)

The Selective 5-Hydroxytryptamine (5-HT)4-Receptor Agonist RS67506 Enhances Lower Intestinal Propulsion in Mice

Yukinori Nagakura, Hiroyuki Ito, Tetsuo Kiso, Yuki Naitoh and Keiji Miyata

Neuroscience Research, Pharmacological Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305, Japan

Abstract: Interactions of gastrointestinal prokinetic benzamides with 5-hydroxytryptamine (5-HT)3 and 5-HT4 receptors and the relation to their effects on gastrointestinal propulsion were investigated. Renzapride and zacopride potently inhibited 5-HT3-receptor-mediated contractions in the guinea pig colon, whereas RS67506 (1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(2-methyl sulphonylamino)ethyl-4-piperidinyl]-1-propanone hydrochloride), a selective 5-HT4-receptor agonist, showed no inhibition. RS67506, renzapride and zacopride all exerted 5-HT4 receptor-mediated relaxation in the carbachol-precontracted rat oesophagus. In mice, RS67506 shortened the whole gut transit time, whereas renzapride and zacopride were reported to prolong it. Gastrointestinal prokinetic benzamides, which are selective for 5-HT4-receptor agonistic over 5-HT3-receptor antagonistic action, may be useful in treating gastrointestinal disorders associated with impaired lower intestinal propulsion such as constipation.

Keywords: 5-HT3 receptor, 5-HT4 receptor, RS67506