Zacopride hydrochloride

Pharmacological properties of a novel gastrointestinal prokinetic benzamide selective for human 5-HT4 receptor versus human 5-HT3 receptor.[Pubmed:10328995]

Pharmacol Res. 1999 May;39(5):375-82.

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.

Effects of 5-HT4-receptor agonists, cisapride, mosapride citrate, and zacopride, on cardiac action potentials in guinea pig isolated papillary muscles.[Pubmed:9213211]

J Cardiovasc Pharmacol. 1997 May;29(5):670-5.

The purpose of this study was to examine the effects of 5-HT4-receptor agonists cisapride, mosapride citrate (mosapride), and zacopride on action potentials (APs) in guinea pig isolated papillary muscles. Cisapride (0.1-3 microM) concentration-relatedly prolonged the duration of APs (APD) without affecting the other AP parameters. Mosapride and its main metabolite M1 (des-4-fluoro-benzyl-mosapride) did not affect APs at 10 microM. Zacopride at 10 microM shortened APD, and the APD-shortening effect was not affect by GR113808 (10 microM), a 5-HT4-receptor antagonist. The cisapride (1 microM)-induced prolongation of APD was not affected by GR113808 (10 microM), ritanserin (10 microM), a 5-HT2A/2C-receptor antagonist, or prazosin (10 microM), an alpha 1-receptor antagonist. The same concentrations of GR113808, ritanserin, and prazosin did not affect APD. Clofilium, a class III antiarrhythmic agent, prolonged APD; the effect was more pronounced at a stimulus frequency of 0.3 Hz than at 2.0 Hz. Cisapride did not exert such reverse use dependence, suggesting that its mechanism of action is different from that of clofilium. These results suggest that cisapride prolongs APD without involvement of 5-HT2, 5-HT4, or alpha 1 receptors. Mosapride is unlikely to induce the prolongation of electrocardiographic QT intervals correlated with the prolongation of APD in isolated ventricular muscles.

Comparison of the 5-HT3 receptor antagonist properties of ICS 205-930, GR38032F and zacopride.[Pubmed:2521513]

J Pharmacol Exp Ther. 1989 Jan;248(1):197-201.

The well-documented 5-HT3 receptor antagonists, ICS 205-930 and GR38032F, have been compared with regard to their inhibitory activity at 5-HT3 receptors to another gastrokinetic agent, zacopride. Zacopride and ICS 205-930 showed similar affinity (-log kB approximately 8.0), whereas GR38032F showed lower affinity (-log ka approximately 7.0) at 5-HT3 receptors in the guinea pig ileum. After i.v. administration to anesthetized rats, zacopride was approximately 10-fold more potent than either ICS 205-930 or GR38032F, which were equipotent as inhibitors of serotonin-induced bradycardia (5-HT3-mediated activation of the von Bezold Jarisch reflex). After oral administration to anesthetized rats, zacopride remained approximately 10-fold more potent than ICS 205-903, which was approximately 2-fold more potent than GR38032F as an inhibitor of serotonin-induced bradycardia. Furthermore, the inhibitory effectiveness of GR38032F persisted for less than 3 hr after oral administration and for less than 15 min after intravenous administration. ICS 205-930 produced maximal inhibition of serotonin-induced bradycardia for over 3 hr with heart rate returning to control values 6 hr after oral administration. Zacopride possessed the longest duration of inhibitory effectiveness in urethane-anesthetized rats with maximal inhibition still apparent 6 hr after oral administration. All three agents inhibited cisplatin-induced emesis after i.v. administration in dogs with zacopride being 10-fold more potent than ICS 205-930 or GR38032F, which were equipotent. These comparative data with three 5-HT3 receptor antagonists indicate that in animals, zacopride was more potent and longer acting than either ICS 205-930 or GR38032F. Furthermore, after oral administration to rats, GR38032F was slightly less potent than ICS 205-930 and possessed the shortest duration of action.

Zacopride: anxiolytic profile in rodent and primate models of anxiety.[Pubmed:2900320]

J Pharm Pharmacol. 1988 Apr;40(4):302-5.

Zacopride, a substituted benzamide derivative, was compared with diazepam in three models of experimental or provoked anxiety. The drug's action (i) in reducing aversion to a brightly lit environment was assessed in mice using a two compartment black and white test box system, (ii) in disinhibiting a suppressed behaviour was measured in the rat social interaction test under high light/unfamiliar conditions and (iii) in antagonizing a defensive response in the marmoset was assessed using the threat of a human presence. Both zacopride and diazepam enhanced exploratory behaviour and social interaction in the mouse and rat models and antagonized the defensive response in the marmoset, zacopride being 100 times more potent than diazepam. It is concluded that the 5-HT3 receptor antagonist, zacopride, alters rodent and primate behaviour in a manner consistent with that of an anxiolytic agent.