SR-57227A - A POTENT AND SELECTIVE AGONIST AT CENTRAL AND PERIPHERAL 5-HT(3) RECEPTORS IN-VITRO AND IN-VIVO

SR 57227A (4-amino-(6-chloro-2-pyridyl)-1 piperidine hydrochloride) is a novel compound with high affinity and selectivity for the 5-HT3 rec eptor. The compound had affinities (IC50) varying between 2.8 and 250 nM for 5-HT3 receptor binding sites in rat cortical membranes and on w hole NG 108-15 cells or their membranes in vitro, assayed under variou s conditions with [H-3]S-zacopride or [H-3]granisetron as radioligand. Like reference 5-HT3 receptor agonists, SR 57227A stimulated the upta ke of [C-14]guanidinium into NG 108-15 cells in the presence of substa nce P (EC50 = 208 +/- 16 nM) and contracted the isolated guinea-pig il eum (EC50 = 11.2 +/- 1.1 mu M), effects that were antagonised by the 5 -HT3 receptor antagonist tropisetron. The agonist effect of SR 57227A was also observed in vivo, as the compound elicited the Bezold-Jarisch reflex in anaesthetised rats (ED50 = 8.3 mug/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 anta gonised 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 refere nce 5-HT3 agonists, SR 57227A bound to 5-HT3 receptors on mouse cortic al membranes after systemic administration (ED50 = 0.39 mg/kg i.p. and 0.85 mg/kg p.o.). These results suggest that SR 57227A is a potent ag onist at peripheral and central 5-HT3 receptors, both in vitro and in vivo. In view of the dearth of 5-HT3 receptor agonists which are capab le 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.