Pharmacological properties of a novel gastrointestinal prokinetic benzamide selective for human 5-HT4 receptor versus human 5-HT3 receptor

Binding properties of gastrointestinal prokinetic benzamides for both clone d human 5-hydroxytryptamine (5-HT)(3) receptors and cloned human 5-HT4 rece ptors were examined and pharmacological properties of YM-53389{(+)-(S)-2-ch loro-5-methoxy-4-[5-(2-piperid methyl)-1,2,4-oxadiazol-3-yl]aniline monohyd rochloride} were characterised in animals. Cisapride, renzapride and zacopr ide inhibited specific binding of [H-3]ramosetron to cloned human 5-HT3 rec eptors, with K-i values of 684, 7.64 and 0.38 nM, respectively. YM-53389, h owever, slightly replaced that (K-i > 10,000 nM). YM-53389, cisapride, renz apride and zacopride replaced specific binding of [H-3]GR 113808 to cloned human 5-HT,receptors, with K-i, values of 54.6, 41.5, 115 and 373 nM, respe ctively. The potency for inhibitory effect of YM-53389 on 5-HT4 receptor-me diated contraction in the guinea-pig isolated colon was very low with pIC(5 0) of 4.7. YM-53389 exerted 5-HT4 receptor-mediated relaxation in the carba chol-precontracted rat isolated oesophagus with pEC(50) of 6.3. In mice, YM -53389 at 10 and 30 mg kg(-1) s.c. significantly shortened whole gut transi t time, in contrast to cisapride, renzapride and zacopride which were repor ted to delay that. YM-53389 had no significant effect on upper gastrointest inal propulsion at doses up to 30 mg kg(-1), s.c. Based on these results, Y M-53389 may surpass existing benzamides in facilitating lower intestinal pr opulsion and benefit patients with gastrointestinal disorders associated wi th impair of intestinal propulsion, such as constipation, based on the sele ctive interaction with human 5-HT4 receptors vs human 5-HT3 receptors. (C) 1999 Academic Press.