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

Pharmacol Res. 1999 May;39(5):375-82. doi: 10.1006/phrs.1998.0454.


Binding properties of gastrointestinal prokinetic benzamides for both cloned human 5-hydroxytryptamine (5-HT)3 receptors and cloned human 5-HT4 receptors were examined and pharmacological properties of YM-53389{(+)-(S)-2-chloro-5-methoxy-4-[5-(2-piperidylmethyl)-1,2, 4-oxadiazol-3-yl]aniline monohydrochloride} were characterised in animals. Cisapride, renzapride and zacopride inhibited specific binding of [3H]ramosetron to cloned human 5-HT3 receptors, with Ki values of 684, 7.64 and 0.38 n m, respectively. YM-53389, however, slightly replaced that (Ki>10,000 n m). YM-53389, cisapride, renzapride and zacopride replaced specific binding of [3H]GR 113808 to cloned human 5-HT4 receptors, with Ki values of 54.6, 41.5, 115 and 373 n m, respectively. The potency for inhibitory effect of YM-53389 on 5-HT3 receptor-mediated contraction in the guinea-pig isolated colon was very low with pIC50 of 4.7. YM-53389 exerted 5-HT4 receptor-mediated relaxation in the carbachol-precontracted rat isolated oesophagus with pEC50 of 6.3. In mice, YM-53389 at 10 and 30 mg kg-1, s.c. significantly shortened whole gut transit time, in contrast to cisapride, renzapride and zacopride which were reported to delay that. YM-53389 had no significant effect on upper gastrointestinal propulsion at doses up to 30 mg kg-1, s.c. Based on these results, YM-53389 may surpass existing benzamides in facilitating lower intestinal propulsion and benefit patients with gastrointestinal disorders associated with impair of intestinal propulsion, such as constipation, based on the selective interaction with human 5-HT4 receptors vs human 5-HT3 receptors.

MeSH terms

  • Animals
  • Benzamides / pharmacology
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cisapride / pharmacology
  • Digestive System / drug effects*
  • Esophagus / drug effects
  • Gastrointestinal Transit / drug effects
  • Guinea Pigs
  • Humans
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Inbred ICR
  • Muscle Contraction / drug effects
  • Muscle Relaxation / drug effects
  • Muscle, Smooth / drug effects
  • Oxadiazoles / pharmacology*
  • Piperidines / pharmacology*
  • Radioligand Assay
  • Rats
  • Rats, Wistar
  • Receptors, Serotonin / drug effects*
  • Receptors, Serotonin, 5-HT3
  • Receptors, Serotonin, 5-HT4
  • Serotonin Antagonists / pharmacology
  • Serotonin Receptor Agonists / pharmacology


  • 2-chloro-5-methoxy-4-(5-(2-piperidylmethyl)-1,2,4-oxadiazol-3-yl)aniline
  • Benzamides
  • Bridged Bicyclo Compounds, Heterocyclic
  • Oxadiazoles
  • Piperidines
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT3
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • Receptors, Serotonin, 5-HT4
  • renzapride
  • zacopride
  • Cisapride