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 vivo

In five fasting, conscious dogs, we compared the prokinetic action of two s elective 5-hydroxytryptamine-4 (5-HT4) receptor agonists with low affinity for 5-HT3 receptors ML10302 (2-piperidinoethyl 4-amino-5-chloro-2-methoxybe nzoate) and SR59768 (2-[(3S)-3-hydroxypiperidino]ethyl 4-amino-5-chloro-2-m ethoxybenzoate) 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 stimulat ed 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); mimickin g the effect of cisapride (303000 nmol/kg i.v.). The maximal effect was ach ieved with the dose of 100 nmol/kg i.v. for both compounds. Similar finding s were obtained in the jejunum. Atropine and GR125487 (1-[2-[(methylsulfony l)amino]ethyl]-4-piperidinyl-methyl 5-fluoro-2-methoxy-1 H-indole-3-carboxy late, selective 5-HT4 receptor antagonist), at doses having no effect per s e, antagonized intestinal prokinesia by maximal doses of ML10302 and SR5976 8. 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, ML 10302 and SR59768 share with cisapride a similar prokinetic action in the c anine duodenum and jejunum in vivo. This effect is mediated by pathways inv olving activation of 5-HT4 and muscarinic receptors. Unlike cisapride, whic h induces tachycardia and prolongs the QT(c) by a mechanism probably unrela ted to 5-HT4 receptor activation, ML10302 and SR59768 are devoid of cardiac effects in this model.