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

抄録

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]GR113808. 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 (K_d=0.28±0.02 nM, B_max=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]GR113808 binding in the ileum (K_i value: 84.2 nM). The presence of mosapride (30 nM) significantly increased the K_d value to 0.44±0.05 nM in the Scatchard analysis of [³H]GR113808 binding. B_max 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 K_i 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.