Disease relevance of Zacopride

• Both zacopride and BMY25801 were effective against emesis and related signs [1].
• 5-HT3 receptor antagonists, zacopride, ICS 205-930 and GR38032F, dose-dependently blocked the tachycardia and pressor response to 2CH3-5-HT [2].
• 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) [3].
• Zacopride decreased the hypercapnia, indicating an improvement in ventilation, whereas 8-OH-DPAT did not affect the hypercapnia and, therefore, did not improve ventilation [4].
• Zacopride and 8-OH-DPAT reverse opioid-induced respiratory depression and hypoxia but not catatonic immobilization in goats [4].

Psychiatry related information on Zacopride

• Locomotor activity was significantly depressed by both radiation (all doses) and zacopride alone (0.03 mg/kg and 0.3 mg/kg) [1].
• The effects of three 5HT3 receptor antagonists: BRL 43964 (0.1 and 1 mg/kg, oral), GR 38032F (0.1 and 1 mg/kg, oral), and zacopride (0.01, 0.1 and 1 mg/kg, IP) were examined in low light test conditions of the social interaction test [5].
• The effects of the 5-HT3 receptor antagonists, zacopride, ondansetron and ICS 205-930, were investigated in an animal model of depression, the learned helplessness test [6].

High impact information on Zacopride

• The rank order of potencies for serotonergic ligands to displace specific [3H]5-HT binding was: 5-carboxamido-tryptamine > methiothepin > metergoline > 5-HT > 8-hydroxy-2-(di-n-propylamino)tetralin > sumatriptan > ketanserin > zacopride [7].
• Effect of the serotonin-4 receptor agonist zacopride on aldosterone secretion from the human adrenal cortex: in vivo and in vitro studies [8].
• The potency of benzamides (cisapride greater than BRL 24924 greater than zacopride greater than BRL 20627 greater than metoclopramide) is similar to their effect of 5-HT4 receptors positively coupled with an adenylate cyclase of fetal mouse colliculi neurons [9].
• In addition, tetrodotoxin abolished the increase in DA release induced by the 5-HT4 agonist (S)- zacopride (100 microM) [10].
• With computer modeling, an initial three-component pharmacophore for specific 5-HT3 receptor ligands ICS-205-930 (1), ondansetron (2), zacopride (3), and 3-[2-(guanidinylmethyl)-4-thiazolyl]indol (4) has been identified [11].

Chemical compound and disease context of Zacopride

• In mouse behavioral studies, ondansetron and R and S zacopride potently inhibited aversive behavior to light (0.0003-30 micrograms/kg, p.o.), when the amount of time spent in the dark and locomotor activity were measured [12].
• 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 [3].
• Emesis induced by cisplatin was abolished by the 5-hydroxytryptamine (5-HT) M-receptor antagonists ICS205-930, zacopride, dazopride and metoclopramide [13].
• Effects of zacopride and BMY25801 (batanopride) on radiation-induced emesis and locomotor behavior in the ferret [1].
• The 5-HT3 receptor antagonists ICS 205-930 and zacopride attenuated cocaine-induced locomotor activity in C57BL/6ByJ mice [14].

Biological context of Zacopride

• This is in contrast to another 5-HT3 receptor antagonist, zacopride, which did produce a marked increase in gastric emptying in rats at doses of 0.1 mg/kg p.o. and higher [15].
• At 0.3 mg/kg p.o., zacopride reliably evoked an 80 to 100% incidence of emesis and a 40 to 80% incidence of defecation [16].
• The involvement of 5-HT3 mechanisms is indicated by a correlation between zacopride and its enantiomers to cause and prevent emesis and their affinity at 5-HT3 binding sites [17].
• Zacopride (1 mg/kg) and ICS 205-930 (50 micrograms/kg) shortened and suppressed, respectively, the inhibition of intestinal spiking activity with early restoration of intestinal motility in both duodenum and jejunum [18].
• The 5-HT3 receptor agonist action of S 21007 was also demonstrated in urethane-anaesthetized rats as this drug (120 micrograms/kg i.v.) triggered the Bezold-Jarisch reflex (rapid fall in heart rate), and this action could be prevented by pretreatment with the potent 5-HT3 receptor antagonist zacopride [19].

Anatomical context of 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 [3].
• 2. Racemic zacopride, and both of the enantiomers, displayed potent 5-HT3 receptor antagonist activity in the isolated vagus nerve and in the von Bezold-Jarisch model [20].
• Zacopride (intragastric, 0.3 mg/kg) or a placebo was given blindly and randomly in the basal state and 15 min before a whole-body 800 cGy 60Co gamma-radiation dose (except for the legs which were partially protected to permit survival of some bone marrow) [21].
• Substitution of the chlorine atom by a radio-iodine in position 5 in the zacopride molecule yielded [125I]iodo-zacopride that bound with high affinity (Kd = 4.3 nM) to 5-HT3 receptors in the rat central nervous system [22].
• In well-washed striatal membranes, neither zacopride nor ICS 205-930 (10(-9)-10(-5) M) inhibited [3H]2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane ([3H]WIN 35,428) (0.3 nM) binding [23].

Associations of Zacopride with other chemical compounds

• 5-HT1P-like responses can be mimicked by 5- and 6-hydroxyindalpine, by another substituted benzamide, the S stereoisomer of zacopride, and by anti-idiotypic antibodies [24].
• The overall pattern of results with zacopride is explained by suggesting that the anxiogenic effects of high doses of zacopride are detectable at low levels of 5-HT function and are due to an agonist action of the S-isomer in the rat at 5-HT3 receptors [25].
• 3. A similar cyclic AMP-dependent blockade of the K+ current was found with renzapride (BRL 24,924) and other 5-HT4 receptor agonists such as cisapride, BIMU 8, zacopride and 5-methoxytryptamine (5-MeOT) [26].
• The '(R) zacopride' site also appeared to be pharmacologically distinct from the 5-HT4 receptor, since 5-HT4 ligands such as renzapride, SDZ 205,557 or RS 23597-190 exhibited low affinities [27].
• The antiemetic and locomotor effects of two substituted benzamides, zacopride and batanopride (BMY25801), were compared in ferrets after bilateral 60Co irradiation at 2, 4 or 6 Gy [1].

Gene context of Zacopride

• In addition, the stimulation of PI turnover by 2-Me-5-HT was antagonized stereospecifically by the 5-HT3 receptor blocker zacopride [28].
• 5HT1c receptor antagonists (mianserin and cyproheptadine), 5-HT3 receptor antagonist (zacopride) and 5-HT4 receptor antagonist (ICS 205-930) increased the latency of audiogenic seizures and decreased the severity of convulsions in young (20-27 days old) DBA/2 mice [29].
• In addition, the 5-HT3 antagonist zacopride failed to attenuate aggression or produce debilitation at any of the doses tested; however, the 5-HT2 antagonist ritanserin inhibited aggressive behavior at a high dose which was not debilitating [30].
• The effect of both agonists was reversed by prior local microinjection of the 5-HT3 receptor antagonists zacopride (100 pmol) and ondansetron (100 pmol), but not by that of the 5-HT2 receptor antagonist ketanserin (10 pmol) or the mixed 5-HT1/5-HT2 receptor antagonist methysergide (100 pmol) [31].
• The racemic 5-HT3 receptor antagonist, zacopride (10-100 micrograms kg-1, i.m.) evoked an emetic response in ferrets [32].

Analytical, diagnostic and therapeutic context of Zacopride

• Similarly, co-administration of either 25-100 micro M LY-278-584 or 10-100 micro M zacopride with 200 mg% EtOH completely blocked EtOH-maintained intracranial self-administration behavior [33].
• Zacopride (at 0.03 mg/kg and 0.3 mg/kg) remained an effective antiemetic in animals that received a bilateral vagotomy, abolishing emesis in four of eight and two of eight ferrets, respectively [1].
• 3. The increase in EEG-energy induced by zacopride (10 micrograms, i.c.v.) was blocked by ICS 205-930 (1 microgram, i.c.v.). Neither the 5-HT3 receptor agonist 2-methyl-5-hydroxytryptamine (30 micrograms, i.c.v.) nor the selective 5-HT3 receptor antagonist MDL 72222 (30 micrograms, i.c.v.) had any effect upon rat EEG [34].
• Neither zacopride nor 8-OH-DPAT reversed etorphine-induced catatonic immobilization [4].
• Microinjection of serotonin (10 nmol) into the NTS of halothane-anaesthetized, paralyzed and artificially ventilated rats produced an increase in MAP and lumbar sympathetic nerve discharge which could be completely prevented by prior local microinjection of zacopride, a potent serotonin3 antagonist (200 pmol) [35].

References