HOMEPRODUCTSSERVICESCOMPANYCONTACTFAQResearchDictionaryPharmaMobileSign Up FREE or Login

Selective 5-hydroxytryptamine3 (5-HT3) receptor blocking activity of KB-R6933, a novel benzimidazole derivative.

Abstract
5-Hydroxytryptamine3 (5-HT3)-receptor blocking activities of KB-R6933 (6-amino-5-chloro-1-isopropyl-2-(4-methyl-1-piperazinyl)-benzimidazole dimaleate) were assessed in vivo and in vitro. Intravenous administration of KB-R6933, granisetron, ondansetron and azasetron inhibited 5-HT-induced bradycardia (von Bezold-Jarisch reflex) in anesthetized rats, with ED50 values of 0.071, 0.71, 4.0 and 0.82 microg/kg, respectively. The inhibitory effect of KB-R6933 at a dose of 0.3 microg/kg lasted for at least 8 hr, whereas those of granisetron at 30 microg/kg, ondansetron at 100 microg/kg and azasetron at 30 microg/kg nearly disappeared within 2-4 hr. Oral administration of KB-R6933 and granisetron also inhibited the bradycardia, with ED50 values of 0.41 and 76.3 microg/kg, respectively. In guinea pig ileum, KB-R6933 concentration-dependently antagonized 5-HT-evoked contraction and reduced the maximal contraction (pK(B)=8.75). Granisetron, ondansetron and azasetron shifted the dose-response curve for 5-HT to higher concentrations with no reduction of maximal contraction, and their pK(B)s were 7.65, 7.00 and 6.29, respectively. In a radioligand receptor binding study, KB-R6933, granisetron, ondansetron and azasetron displaced [3H]GR65630 binding to rat entorhinal cortex membrane, with Ki values of 0.066, 0.99, 2.70 and 2.5 nM, respectively. On the other hand, KB-R6933 exhibited negligible affinities for other receptors or binding sites tested, except for a weak affinity for the cholinergic M1-receptor, even at concentrations up to 10 microM. These results suggest that KB-R6933 is a potent and selective 5-HT3-receptor antagonist with a longer duration of action than those of existing 5-HT3-receptor antagonists.
AuthorsA Ozaki, Y Fujishima, T Sukamoto
JournalJapanese journal of pharmacology (Jpn J Pharmacol) Vol. 80 Issue 1 Pg. 25-32 (May 1999) ISSN: 0021-5198 [Print] JAPAN
PMID10446753 (Publication Type: Journal Article)
Chemical References
  • Benzimidazoles
  • Imidazoles
  • Indoles
  • KB R6933
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT3
  • Serotonin Antagonists
  • Tritium
  • GR 65630
Topics
  • Animals
  • Benzimidazoles (chemistry, pharmacology, therapeutic use)
  • Binding, Competitive (drug effects)
  • Bradycardia (drug therapy)
  • Guinea Pigs
  • Ileum (drug effects, physiology)
  • Imidazoles (pharmacology)
  • Indoles (pharmacology)
  • Male
  • Muscle Contraction (drug effects)
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Serotonin (metabolism)
  • Receptors, Serotonin, 5-HT3
  • Serotonin Antagonists (pharmacology, therapeutic use)
  • Tritium

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!


Choose Username:
Email:
Password:
Verify Password: