Affinity of Mosapride Citrate, a New Gastroprokinetic Agent, for 5-HT4 Receptors in Guinea Pig Ileum

• Published in: Japanese journal of pharmacology Vol. 77; no. 1; pp. 53 - 60
• Main Authors: Yoshikawa, Takashi, Yoshida, Naoyuki, Mine, Yukiko, Hosoki, Kanoo
• Format: Journal Article
• Language: English
• Published: Japan The Japanese Pharmacological Society 1998
• Subjects: 5-Hydroxytryptamine (5-HT) 4 receptor; Animals; Benzamides - metabolism; Binding, Competitive; Dopamine Antagonists - metabolism; Electric Stimulation; Gastrointestinal tract; Gastroprokinetic agent; Guinea Pigs; Ileum - metabolism; Ileum - physiology; In Vitro Techniques; Indoles - metabolism; Male; Morpholines - metabolism; Mosapride citrate; Muscle Contraction; Radioligand Assay; Radioligand binding; Receptors, Serotonin - metabolism; Receptors, Serotonin, 5-HT4; Serotonin Antagonists - metabolism; Sulfonamides - metabolism; Tritium; 5-Hydroxytryptamine (5-HT) 4 receptor; Gastrointestinal tract; Gastroprokinetic agent; Radioligand binding; Mosapride citrate
• ISSN: 0021-5198; 1347-3506
• DOI: 10.1254/jjp.77.53

We examined the binding affinity of mosapride citrate (mosapride) (4-amino-5-chloro-2-ethoxy-N-{[4-(4-fluorobenzyl)-2-morpholinyl]methyl}benzamide citrate), a novel gastroprokinetic agent, for the 5-hydroxytryptamine (5-HT) 4 receptors in guinea pig ileum using a selective 5-HT4-receptor radioligand, [3H]GR 113808. In membrane preparations from longitudinal muscle with myenteric plexus in guinea pig ileum, specific [3H]GR113808 binding revealed a single saturable site of high affinity (Kd = 0.28±0.02 nM, Bmax = 45±3 fmol/mg protein). Mosapride and other 5-HT4-receptor agonists inhibited the specific binding of [3H]GR113808 in guinea pig ileum. The 5-HT4 agonists examined displayed the following inhibition potency order: BIMU-8 > cisapride > mosapride > renzapride > 5-HT > zacopride > metoclopramide. Mosapride exhibited monophasic inhibition of the specific [3H]GR 113808 binding in the ileum (Ki value: 84.2 nM). The presence of mosapride (30 nM) significantly increased the Kd value to 0.44±0.05 nM in the Scatchard analysis of [3H]GR113808 binding. Bmax of [3H]GR113808, however, was not affected (48±4 fmol/mg protein) by mosapride. As for the affinity of mosapride, the addition of GppNHp (100 μM) slightly increased the Ki value to 104 nM. These results indicate that mosapride has an affinity for 5-HT4 receptors in guinea pig ileum in the radioligand binding study.