Comparison of the effects of trimebutine and YM114 (KAE-393), a novel 5-HT3 receptor antagonist, on stress-induced defecation.

Abstract

YM114 (KAE-393), (R)-5-[(2,3-dihydro-1-indolyl)carbonyl]-4,5,6,7- tetrahydro-1H-benzimidazole hydrochloride, is a derivative of YM060, a potent 5-HT3 receptor antagonist. We investigated the effects of YM114 on 5-HT3 receptors, both in vitro and in vivo, and on bowel dysfunction induced by restraint stress, 5-HT and thyrotropin-releasing hormone (TRH), and compared them with the effect of trimebutine. YM114 dose dependently inhibited the reduction in heart rate induced by 5-HT (30 micrograms/kg i.v.) in rats (ED50 = 0.31 micrograms/kg i.v.), and the potency of YM114 was almost the same as that of the racemate. The S-form of YM114 also inhibited 5-HT-induced bradycardia, but 1350 times less potent than the R-form. YM114 and its S-form inhibited [3H]GR65630 binding to N1E-115 cell membranes in a concentration-dependent manner with Ki values of 0.341 and 616 nM, respectively, showing the isomeric activity ratio (R-/S-form) of YM114 to be much greater (1800). YM114 antagonized 5-HT-induced depolarization of the nodose ganglion (EC50 = 1.39 nM). Trimebutine (1 mg/kg i.v.) failed to inhibit 5-HT-induced bradycardia, implying that it does not possess 5-HT3 receptor antagonistic activity. YM114 significantly and dose dependently prevented restraint stress-, 5-HT- and TRH-induced increases in fecal pellet output, and restraint stress- and 5-HT-induced diarrhea in rats and mice (ED50 = 6.9, 72.5, 154.6, 9.7 and 52.4 micrograms/kg p.o., respectively). Trimebutine significantly prevented stress- and 5-HT-induced diarrhea (ED50 = 29.4 and 87.3 mg/kg p.o., respectively), but only partially affected stress-, 5-HT- and TRH-induced increases in fecal pellet output. Thus, YM114 is a potent and stereoselective 5-HT3 receptor antagonist with much greater protective effects against stress-induced defecation than trimebutine.

• Authors: K Miyata, H Ito, M Yamano, K Hidaka, T Kamato, A Nishida, H Yuki
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 250 Issue 2 Pg. 303-10 (Dec 07 1993) ISSN: 0014-2999 [Print] Netherlands
• PMID: 8112388 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Benzimidazoles
• Imidazoles
• Indoles
• Serotonin Antagonists
• GR 65630
• YM 114
• Serotonin
• Thyrotropin-Releasing Hormone
• Castor Oil
• Dinoprostone
• Trimebutine

Topics

• Animals
• Benzimidazoles (pharmacology)
• Castor Oil
• Cell Membrane (drug effects, metabolism)
• Defecation (drug effects)
• Diarrhea (chemically induced, prevention & control)
• Dinoprostone (pharmacology)
• Heart Rate (drug effects)
• Imidazoles (pharmacokinetics)
• Indoles (pharmacokinetics)
• Male
• Mice
• Mice, Inbred ICR
• Nodose Ganglion (drug effects)
• Rabbits
• Rats
• Rats, Wistar
• Serotonin (pharmacology)
• Serotonin Antagonists
• Stress, Psychological (psychology)
• Thyrotropin-Releasing Hormone (pharmacology)
• Trimebutine (pharmacology)