INTERACTION OF S-21007 WITH 5-HT3 RECEPTORS - IN-VITRO AND IN-VIVO CHARACTERIZATION

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 investigat ed using biochemical, electrophysiological and functional assays. Bind ing studies using membranes from N1E-115 neuroblastoma cells showed th at 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 [ C-14]guanidinium (EC(50) similar to 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-H T3 receptor agonists (phenylbiguanide and 3-chloro-phenylbiguanide), S 21007 (EC(50) = 27 mu M) produced a rapid inward current in N1E-115 c ells. The 5-HT3 receptor agonist action of S 21007 was also demonstrat ed in urethane-anaesthetized rats as this drug (120 mu g/kg i.v.) trig gered the Bezold-Jarisch reflex (rapid fall in heart rate), and this a ction could be prevented by pretreatment with the potent 5-HT3 recepto r antagonist zacopride. Finally, in line with its 5-HT3 receptor agoni st properties, S 21007 also triggered emesis in the ferret. Evidence f or 5-HT3 receptor antagonist-like properties of S 21007 was also obtai ned in some of there experiments since previous exposure to this compo und prevented both the 5-HT-induced current in N1E-115 cells and the B ezold-Jarisch reflex elicited by an i.v. bolus of 5-HT (30 mu g/kg) in urethane-anaesthetized rats. These data suggest that S 21007 is a sel ective 5-HT3 receptor agonist which can exhibit antagonist-like proper ties either by triggering a long lasting receptor desensitization or b y a partial agonist activity at 5-HT3 receptors in some tissues.