Vol. 288, Issue 3, 1045-1052, March 1999

Intestinal Prokinesia by Two Esters of 4-Amino-5-Chloro-2-Methoxybenzoic Acid: Involvement of 5-Hydroxytryptamine-4 Receptors and Dissociation from Cardiac Effects In Vivo¹

Francesca Crema, Chiara Modini, Tiziano Croci², Michel Langlois³ and Fabrizio de Ponti

Department of Internal Medicine and Therapeutics, Section of Pharmacology and Toxicology, University of Pavia, Pavia PV, Italy

In five fasting, conscious dogs, we compared the prokinetic action of two selective 5-hydroxytryptamine-4 (5-HT₄) receptor agonists with low affinity for 5-HT₃ receptors ML10302 (2-piperidinoethyl 4-amino-5-chloro-2-methoxybenzoate) and SR59768 (2-[(3S)-3-hydroxypiperidino]ethyl 4-amino-5-chloro-2-methoxybenzoate) in the duodenum and jejunum, using cisapride as a reference compound. Heart rate and rate-corrected QT (QT_c) also were monitored to assess whether or not the cardiac effects of cisapride are shared by other 5-HT₄ receptor agonists. Both ML10302 and SR59768 dose-dependently stimulated spike activity in the duodenum with similar potencies (dose range, 3-300 nmol/kg i.v.; ED₅₀ values: 24 and 23 nmol/kg i.v., respectively), mimicking the effect of cisapride (30-3000 nmol/kg i.v.). The maximal effect was achieved with the dose of 100 nmol/kg i.v. for both compounds. Similar findings were obtained in the jejunum. Atropine and GR125487 (1-[2-[(methylsulfonyl)amino]ethyl]-4-piperidinyl-methyl 5-fluoro-2-methoxy-1H-indole-3-carboxylate, selective 5-HT₄ receptor antagonist), at doses having no effect per se, antagonized intestinal prokinesia by maximal doses of ML10302 and SR59768. Neither ML10302 nor SR59768 had any effect on heart rate or QT_c at any of the doses tested, whereas cisapride, at the highest dose (3000 nmol/kg), induced tachycardia and lengthened the QT_C (p < .01). In conclusion, ML10302 and SR59768 share with cisapride a similar prokinetic action in the canine duodenum and jejunum in vivo. This effect is mediated by pathways involving activation of 5-HT₄ and muscarinic receptors. Unlike cisapride, which induces tachycardia and prolongs the QT_c by a mechanism probably unrelated to 5-HT₄ receptor activation, ML10302 and SR59768 are devoid of cardiac effects in this model.