title: 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.
authors.affiliation: IRIS, Courbevoie, France.
authors.forename: P
authors.initials: P
authors.lastname: Delagrange
authors.forename: M B
authors.initials: MB
authors.lastname: Emerit
authors.forename: N
authors.initials: N
authors.lastname: Merahi
authors.forename: C
authors.initials: C
authors.lastname: Abraham
authors.forename: P
authors.initials: P
authors.lastname: Morain
authors.forename: S
authors.initials: S
authors.lastname: Rault
authors.forename: P
authors.initials: P
authors.lastname: Renard
authors.forename: B
authors.initials: B
authors.lastname: Pfeiffer
authors.forename: B
authors.initials: B
authors.lastname: Guardiola-Lemaître
authors.forename: M
authors.initials: M
authors.lastname: Hamon
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002462:Cell Membrane / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D017294:Ondansetron / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
chemical_list: D010879:Piperazines; D011719:Pyrazines; D011985:Receptors, Serotonin; C106046:S 21007; D017366:Serotonin Receptor Agonists; D017294:Ondansetron