Cisapride and a structural analogue, R 76,186, are 5-hydroxytryptamine4 (5-HT4) receptor agonists on the guinea-pig colon ascendens

Naunyn Schmiedebergs Arch Pharmacol. 1993 May;347(5):464-70. doi: 10.1007/BF00166736.


The purpose of this study was to investigate whether the effects of cisapride and its close structural analogue R 76,186 on the isolated guinea-pig colon ascendens, are mediated through 5-HT4 receptors. Both cisapride and R 76,186 induced contractions in a concentration-dependent fashion, giving monophasic concentration-response curves (cisapride: EC50 = 1.1 x 10(-7) M, maximum effect = 40.3% of methacholine-induced (3 x 10(-7) M) contractions; R 76,186: EC50 = 2.4 x 10(-8) M, maximum effect = 52.1%). Blockade of either 5-HT2 or 5-HT3 receptors did not affect the responses to cisapride. However, tropisetron (in 5-HT4 receptor-blocking concentrations), and DAU 6285 and SDZ 205-557, two novel selective 5-HT4 receptor antagonists, depressed the concentration-response curve to cisapride (to about 50%), and the curve to R 76,186 was shifted to the right. The apparent pA2 values were 6.6 (tropisetron), 6.3 (DAU 6285), and 7.5 (SDZ 205-557). However, none of these antagonisms was purely competitive as higher concentrations of these antagonists depressed the curve to R 76,186. Desensitization of the 5-HT4 receptor with 5-methoxytryptamine (5-MeOT) inhibited the responses to cisapride, and abolished those to R 76,186. The contractions to cisapride and R 76,186 were sensitive to mutual antagonism, depressing their concentration-response curves.

Conclusions: Both cisapride and R 76,186 mediate their contractile effects in the guinea-pig colon ascendens through agonism at the 5-HT4 receptor, though cisapride also uses a non-5-HT mechanism. R 76,186 is a selective and potent 5-HT4 receptor agonist.

MeSH terms

  • 4-Aminobenzoic Acid / pharmacology
  • Animals
  • Cisapride
  • Colon / drug effects*
  • Colon / metabolism
  • Female
  • Guinea Pigs
  • Male
  • Muscle Contraction / drug effects
  • Muscle, Smooth / drug effects*
  • Muscle, Smooth / metabolism
  • Piperidines / pharmacology*
  • Receptors, Serotonin / drug effects*
  • Receptors, Serotonin / metabolism
  • Serotonin / metabolism
  • Serotonin Antagonists / pharmacology*
  • Serotonin Receptor Agonists / pharmacology*
  • para-Aminobenzoates


  • Piperidines
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • para-Aminobenzoates
  • R 76186
  • 2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino)ethyl ester
  • Serotonin
  • 4-Aminobenzoic Acid
  • Cisapride