Comparison of gastrokinetic effects of AS-4370, cisapride and BRL24924

Karasawa, Tadahiko; Yoshida, Naoyuki; Furukawa, K.; Omoya, Hiroko; Ito, Tsugutaka

doi:10.1016/0014-2999(90)93708-x

Cited by 24 publications

(14 citation statements)

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“…Moreover, the different effects of cisapride and mosapride on colonic motility might be explained by a distinct receptor binding affinity. Although mosapride exhibits no affinity for the D 2 , adrenaline ␣ 1 , adrenaline ␣ 2 , 5-HT 1 , and 5-HT 2 receptors except for the strong affinity for the 5-HT 4 receptor, cisapride possesses affinity for the D 2 , 5-HT 2 , ␣ 1 , and muscarinic receptors as well as the 5-HT 4 receptor (Yoshida et al, 1989;Karasawa et al, 1990;Briejer et al, 1995). Recently, a 5-HT 4 receptor partial agonist, tegaserod, was reported to stimulate colonic motility in dogs (Appel et al, 1996;Nguyen et al, 1997) and accelerate propulsion in isolated guinea pig colon (Jin et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Stimulatory Action of Itopride Hydrochloride on Colonic Motor Activity in Vitro and in Vivo

Tsubouchi

Saito²,

Mizutani³

et al. 2003

The Journal of Pharmacology and Experimental Therapeutics

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Section: Discussionmentioning

confidence: 99%

Stimulatory Action of Itopride Hydrochloride on Colonic Motor Activity in Vitro and in Vivo

Tsubouchi

Saito²,

Mizutani³

et al. 2003

The Journal of Pharmacology and Experimental Therapeutics

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“…Released 5-HT, in turn, causes stimulation of 5-HT3 receptors located in the afferent vagal fibers, thereby eliciting the vomiting reflex (35 -37). Cisplatin is also reported to delay gastric emptying in rats (22,38). Although the mechanism by which cisplatin slows gastric emptying has not yet been established, a contribution by 5-HT3 receptor has been suggested (38).…”

Section: Discussionmentioning

confidence: 99%

“…In another series of experiments to evaluate the gastroprokinetic effect of test drugs under delayed conditions, the rats were treated with cisplatin at an intraperitoneal dose of 10 mg/kg 30 min before glass bead administration (22) and killed by cervical dislocation 30 min after the beads were given. Test drugs or vehicle were intravenously injected 15 min before cisplatin.…”

Section: Gastric Emptying In Ratsmentioning

confidence: 99%

Effect of Serotonin (5-HT)3-Receptor Antagonists YM060, YM114 (KAE-393), Ondansetron and Granisetron on 5-HT4 Receptors and Gastric Emptying in Rodents

Miyata

Yamano

Kamato

et al. 1995

Japanese Journal of Pharmacology

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ABSTRACT-We investigated the effects of YM060 {(R)-5-[(1-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride} and YM114 (KAE-393) {(R)-5-[(2,3-dihydro-l-indolyl)-carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride} on 5-HT4 receptors and gastric emptying in normal and cisplatin-treated rats and compared results with those for ondansetron and granisetron. YM060, YM114, ondansetron and granisetron dose-dependently inhibited the specific binding of-4-piperidin-yl]methyl 1-methyl-lH-indole-3-carboxylate} in guinea pig striatum, with pK; values of 5.53, 5.13, 5.21 and 5.63, respectively. According to the pK; values reported in 5-HT3-receptor binding of [3H]GR65630 to rat cortical membranes, the affinity of YM060, YM114, ondansetron and granisetron for 5-HT4 receptors was approximately 5, 5, 3.5 and 3.5 log units lower than that for 5-HT3 receptors, respectively. In the guinea pig longitudinal muscle with myenteric plexus and rat esophageal tunica muscularis mucosae, YM060 and YM114 showed neither 5-HT4-agonistic nor antagonistic properties. Although ondansetron produced concentration-dependent increases in the magnitude of the twitch response in longitudinal muscle, it did not possess 5-HT3-and 5-HT4-agonistic activity. Granisetron antagonized 5-HT-induced relaxation of the rat esophagus with an apparent pA2 value of 5.39. Intravenous YM060, YM114, ondansetron and granisetron significantly enhanced gastric emptying of glass beads and improved cisplatin-induced slowing of gastric emptying in rats. These results indicate that the selectivity of YM060 and YM 114 for 5-HT3 receptors is higher than that of ondansetron and granisetron and that these 5-HT3 antagonists have gastroprokinetic activity in normal and cisplatin-treated rats without affecting 5-HT4 receptors. Keywords: YM060, YM114 (KAE-393), 5-HT4 receptor, Gastric emptyingThe use of cisplatin in the treatment of cancer is usually accompanied by the side effects of severe nausea and vomiting. Recently, a number of compounds that inhibit these side effects have been developed. These compounds all act via inhibition of 5-HT3 receptors. YM060 and YM114 (KAE-393) are 4,5,6,7-tetrahydrobenzimidazole derivatives. These compounds have been reported to be potent and selective 5-HT3-receptor antagonists of 5-HTinduced von Bezold-Jarisch reflex in rats (1, 2), contraction of the guinea pig colon (3, 4) and depolarization of the rabbit nodose ganglion (2, 5).To date, a number of 5-HT3-receptor antagonists have been synthesized. Among these, tropisetron (6), cisapride (7), zacopride (8), ondansetron (9) and renzapride (10) have been reported to possess gastroprokinetic activities in rats or guinea pigs. Compounds that block the 5-HT3 receptor are therefore suggested to increase the rate of gastric emptying.Recent studies have revealed that the peripheral 5-HT4-receptor subtype is involved in the control of gastrointestinal motility through the release of acetylcholine (11-13) and that 5-HT4-receptor agonists facilitate gastric emptying (14, 1...

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“…The effect of substituents on the benzene moiety of the 1H-indazole ring was then examined. In general, the substituents investigated did not provide any improvement (77)(78)(79)(80)(81)(82)(83).…”

Section: Structure-activity Relationships Of Hexahydro-14-diazepinylmentioning

confidence: 86%

“…In radioligand binding assay, metoclopramide and cisapride had high affinity for dopamine D 2 receptor sites, with IC 50 values of 0.48 and 0.39 M, respectively. On the other hand, mosapride had no affinity for dopamine D 2 receptor sites, even at 100 M. 51,72,77 The lack of a dopamine D 2 receptor-blocking property of mosapride was confirmed by the following in vivo experiments. Mosapride, unlike metoclopramide, neither antagonized apomorphine-induced emesis in dogs nor dopamine-induced suppression of antral motor activity in conscious dogs.…”

Section: B Pharmacological Profiles Of Mosapridementioning

confidence: 92%

Nitrogen-containing heteroalicycles with serotonin receptor binding affinity: Development of gastroprokinetic and antiemetic agents

1999

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To obtain gastroprokinetic agents with more potent and selective activity than metoclopramide and cisapride, a series of N‐(4‐benzyl‐2‐morpholinylmethyl)benzamides were designed and prepared. Their synthesis and structure‐activity relationships were described. As a result, mosapride was selected as a promising candidate for potent gastroprokinetic activity with selective 5‐HT4 receptor agonistic activity. As an extension to this project, the novel benzamide and the carboxamide derivatives having 1‐benzyl‐4‐methylhexahydro‐1,4‐diazepine ring in the amine moiety were prepared and evaluated for 5‐HT3 receptor antagonistic activity. DAT‐582 was identified as an antiemetic agent in cancer chemotherapy. The asymmetric synthesis of DAT‐582 and the SAR studies were briefly reviewed. In further modifications of the N‐(1‐benzyl‐4‐methylhexahydro‐1,4‐diazepin‐6‐yl)benzamides, the novel nicotinamides with 1‐ethyl‐4‐methylhexahydro‐1,4‐diazepin ring were found to have potent 5‐HT3 and dopamine D2 and D3 receptor antagonistic activities and to show weak central nervous system depression and extrapyramidal syndrome. After extensive SARs, AS‐8112 was selected as a broad antiemetic agent. © 1999 John Wiley & Sons, Inc. Med Res Rev, 19, No. 1, 25–73, 1999.

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Comparison of gastrokinetic effects of AS-4370, cisapride and BRL24924

Cited by 24 publications

References 0 publications

Stimulatory Action of Itopride Hydrochloride on Colonic Motor Activity in Vitro and in Vivo

Stimulatory Action of Itopride Hydrochloride on Colonic Motor Activity in Vitro and in Vivo

Effect of Serotonin (5-HT)3-Receptor Antagonists YM060, YM114 (KAE-393), Ondansetron and Granisetron on 5-HT4 Receptors and Gastric Emptying in Rodents

Nitrogen-containing heteroalicycles with serotonin receptor binding affinity: Development of gastroprokinetic and antiemetic agents

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