SR 57227A: a potent and selective agonist at central and peripheral 5-HT3 receptors in vitro and in vivo.

Abstract SR 57227A (4-amino-(6-chloro-2-pyridyl)-1 piperidine hydrochloride) is a novel compound with high affinity and selectivity for the 5-HT 3 receptor. The compound had affinities (IC 50 ) varying between 2.8 and 250 nM for 5-HT 3 receptor binding sites in rat cortical membranes and on whole NG 108-15 cells or their membranes in vitro, assayed under various conditions with [ 3 H]S-zacoprode or [ 3 H]granisetron as radioliganf. Like references 5-HT 3 receptor agonists, SR 57227A stimulated the uptake of [ 14 C]guanidium into NG 108-15 cells in the presence of substance P EC 50 = 208 ± 16 nM ) and contracted the isolated guinea-pig ileum (EC 50 = 11.2±1.1 μ M), effects that were effects that were antagonised by the 5-HT 3 receptor antagonists tropisetron. The agonist effect of SR 57227A was also observed in vivo, as the compound elicited the Bezold-Jarisch reflex in anaesthetised rats (ED 50 = 8.3 μ g/kg i.v.), an effect that was blocked by tropisetron and R,S-zacopride, but not by methysergide. When injected unilaterally into the mouse striatum, SR 57227A, like 2-methyl-5-HT, elicited contralateral turning behaviour which was antagonised by ondansetron. Furthermore, microiontophoretic application of SR 57227A markedly inhibited the firing rate of rat cortical neurones, an effect antagonised by tropisetron. Finally, in contrast to reference 5-HT 3 agonists, SR 57227A bound to 5-HT 3 receptors on mouse cortical membranes after systenic administration (ED 50 = 0.39 mg/kg i.p. and 0.85 mg/kg p.o.). These results suggest that SR 57227A is a potent agonist at peripheral and central 5-HT 3 receptors, both in vitro and in vivo. In view of the dearth of 5-HT 3 receptor agonists which are capable of crossing the blood-brain barrier, SR 57227A may be useful in the characterisation of the neuropharmacological effects produced by the stimulation of these receptors.