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Interaction of S 21007 with 5-HT3 receptors. In vitro and in vivo characterization.

Abstract
The interaction of S 21007 [5-(4-benzyl piperazin-1-yl)4H pyrrolo [1,2-a]thieno[3,2-e]pyrazine] with serotonin 5-HT3 receptors was investigated using biochemical, electrophysiological and functional assays. Binding studies using membranes from N1E-115 neuroblastoma cells showed that S 21007 is a selective high affinity (IC50 = 2.8 nM) 5-HT3 receptor ligand. As expected of an agonist, S 21007 stimulated the uptake of [14C]guanidinium (EC50 approximately 10 nM) in NG 108-15 cells exposed to substance P, and this effect could be prevented by the potent 5-HT3 receptor antagonist ondansetron. In addition, like 5-HT and other 5-HT3 receptor agonists (phenylbiguanide and 3-chloro-phenylbiguanide), S 21007 (EC50 = 27 microM) produced a rapid inward current in N1E-115 cells. 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. Finally, in line with its 5-HT3 receptor agonist properties, S 21007 also triggered emesis in the ferret. Evidence for 5-HT3 receptor antagonist-like properties of S 21007 was also obtained in some of these experiments since previous exposure to this compound prevented both the 5-HT-induced current in N1E-115 cells and the Bezold-Jarisch reflex elicited by an i.v. bolus of 5-HT (30 micrograms/kg) in urethane-anaesthetized rats. These data suggest that S 21007 is a selective 5-HT3 receptor agonist which can exhibit antagonist-like properties either by triggering a long lasting receptor desensitization or by a partial agonist activity at 5-HT3 receptors in some tissues.
AuthorsP Delagrange, M B Emerit, N Merahi, C Abraham, P Morain, S Rault, P Renard, B Pfeiffer, B Guardiola-Lemaître, M Hamon
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 316 Issue 2-3 Pg. 195-203 (Dec 05 1996) ISSN: 0014-2999 [Print] Netherlands
PMID8982686 (Publication Type: Journal Article)
Chemical References
  • Piperazines
  • Pyrazines
  • Receptors, Serotonin
  • S 21007
  • Serotonin Receptor Agonists
  • Ondansetron
Topics
  • Animals
  • Binding, Competitive
  • Cell Membrane (drug effects)
  • Dose-Response Relationship, Drug
  • In Vitro Techniques
  • Ondansetron (pharmacology)
  • Piperazines (pharmacology)
  • Pyrazines (pharmacology)
  • Rats
  • Receptors, Serotonin (drug effects)
  • Serotonin Receptor Agonists (pharmacology)

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