GYKI-46903, A NONCOMPETITIVE ANTAGONIST FOR 5-HT3 RECEPTORS

The effects of GYKI-46 903 ndo-4-propionyloxy-6-(4-fluorophenyl)-1-aza bicyclo [3.3.1]non-6-ene HCl), on 5-HT3 receptors have been studied an d compared with ondansetron in peripheral organs in vitro and in vivo, and in a receptor binding assay in membranes prepared from rat cerebr al cortex. GYKI-46 903 was found to be a non-competitive antagonist at 5-HT3 receptors present in non-stimulated longitudinal muscle strip o f guinea-pig ileum (pD(2)' against serotonin=5.54), and also in 5-meth oxytryplamine-pretreated electrically stimulated ileal preparations (p D(2)' against serotonin-5.26). On the contrary, ondansetron was found to be a competitive antagonist for 5-HT3 receptors; the pA(2) value ag ainst serotonin was 7.40 in non-stimulated ileum, and it was 7.08 in e lectrically stimulated ideal preparation pretreated with 5-methoxytryp tamine. In displacement studies, the pIC(50) values of GYKI-46 903, wh en administered by intravenous infusion, antagonized the decrease in h eart rate evoked by serotonin (Bezold-Jarisch reflex) in anaesthetized rats, and the maximal reversal was less than 50%. This was in strikin g contrast with ondansetron, which, after intavenous injection, comple tely antagonized the serotonin-induced bradycardia with an ID50 value of 3.28 ug/kg. These data classify GYKI-46 903 as a non-competitive an tagonist for 5-HT3 receptors.