AIMTo study the effect of S-21007, a 5-HT3 partial agonist in different animal models of anxiety in mice.METHODSS-21007 effects were evaluated in the behavior tests after intraperitoneal and oral acute treatment or in the light/dark test after both acute and chronic treatments.RESULTSS-21007 presented anxiolytic-like properties after acute administration in the light/dark box test, the mirrored chamber test, and the elevated plus-maze at low doses 10 ng.kg(-1)-100 micrograms.kg-1, 1-100 micrograms.kg-1 and 10-100 micrograms.kg-1, respectively. In the light/dark box test, S-21007 was active orally after acute treatment at 100 ng.kg(-1)-10 mg.kg-1 and after chronic treatment (14 d) at 1-10 micrograms.kg-1. S-21007 was devoid of sedative or stimulatory effects.CONCLUSIONS-21007 exhibited anxiolytic-like properties. The mechanism of action may be a desensitization of 5-HT3 receptor or an antagonist activity on the 5-HT3 receptors.

01 Dec 1997·Life SciencesQ3 · MEDICINE

[11C]S21007, A PUTATIVE PARTIAL AGONIST FOR 5-HT3 RECEPTORS PET STUDIES. RAT AND PRIMATE IN VIVO BIOLOGICAL EVALUATION.

Q3 · MEDICINE

Article

Author: Baron, J. C. ; Mickala, P. ; Blaizot, X. ; Besret, L. ; Guilloue, S. ; Rault, S. ; Dauphin, F. ; Gourand, F. ; Barbelivien, A. ; Petit-Taboue, M. C. ; Barre, L. ; Young, A. R. ; Dhilly, M.

We recently labeled with carbon-11, a high affinity, selective, 5-HT3 receptor (5-HT3R) ligand, S21007, for potential positron emission tomography (PET) applications. To evaluate the in vivo binding properties of [11C]S21007, its brain regional distribution, tissue and plasma pharmacokinetics and plasma metabolisation were characterized. To circumvent the problem of highly discrete brain localization of the 5-HT3R (area postrema, hippocampus), we designed an original approach combining high-resolution imaging techniques (ex vivo phosphor plate autoradiography and MRI-guided coronal PET in the rat and baboon, respectively). After i.v. injection of trace amounts of [11C]S21007 to rats, phosphorimager autoradiography failed to reveal in vivo specific binding to, nor selectivity for 5-HT3R-rich areas. PET studies in the baboon showed consistent results, i.e., there was no selective accumulation of [11C]S21007 in the area postrema or hippocampus, and neither displacement nor presaturation with cold S21007 resulted in significant changes in tissue distribution or kinetics of [11C]S21007.

01 Dec 1996·European Journal of PharmacologyQ3 · MEDICINE

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

Q3 · MEDICINE

Article

Author: Abraham, Christine ; Pfeiffer, Bruno ; Guardiola-Lemaitre, Beatrice ; Morain, Philippe ; Renard, Pierre ; Merahi, Nacera ; Delagrange, Philippe ; Emerit, M. Boris ; Rault, Sylvain

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Vomiting	Discovery	FR	Servier Pharmaceuticals LLCStartup	-

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