title: GYKI-46 903, a non-competitive antagonist for 5-HT3 receptors.
abstract: The effects of GYKI-46 903 ((+)endo-4-propionyloxy-6-(4-fluorophenyl)-1-azabicyclo [3.3.1]non-6-ene HCl), on 5-HT3 receptors have been studied and compared with ondansetron in peripheral organs in vitro and in vivo, and in a receptor binding assay in membranes prepared from rat cerebral cortex. GYKI-46 903 was found to be a non-competitive antagonist at 5-HT3 receptors present in non-stimulated longitudinal muscle strip of guinea-pig ileum (pD2' against serotonin = 5.54), and also in 5-methoxytryptamine-pretreated electrically stimulated ileal preparations (pD2' against serotonin = 5.26). On the contrary, ondansetron was found to be a competitive antagonist for 5-HT3 receptors; the pA2 value against serotonin was 7.40 in non-stimulated ileum, and it was 7.08 in electrically stimulated ileal preparation pretreated with 5-methoxytryptamine. In displacement studies, the pIC50 values of GYKI-46 903 and ondansetron against [3H]granisetron binding to rat cerebral cortex membranes were 6.91 and 8.58 respectively. GYKI-46 903, when administered by intravenous infusion, antagonized the decrease in heart rate evoked by serotonin (Bezold-Jarisch reflex) in anaesthetized rats, and the maximal reversal was less than 50%. This was in striking contrast with ondansetron, which, after intravenous injection, completely antagonized the serotonin-induced bradycardia with an ID50 value of 3.28 ug/kg. These data classify GYKI-46 903 as a non-competitive antagonist for 5-HT3 receptors.
authors.affiliation: Institute for Drug Research, Budapest, Hungary.
authors.forename: V
authors.initials: V
authors.lastname: Csillik-Perczel
authors.forename: A
authors.initials: A
authors.lastname: Bakonyi
authors.forename: T
authors.initials: T
authors.lastname: Yemane
authors.forename: B
authors.initials: B
authors.lastname: Vitalis
authors.forename: E
authors.initials: E
authors.lastname: Horvath
authors.forename: S
authors.initials: S
authors.lastname: Solyom
authors.forename: J I
authors.initials: JI
authors.lastname: Szekely
authors.forename: L G
authors.initials: LG
authors.lastname: Harsing
mesh_terms: D008735:5-Methoxytryptamine / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D001919:Bradycardia / Q000188:drug therapy; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004558:Electric Stimulation; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D017294:Ondansetron / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; C103284:GYKI 46903; D008735:5-Methoxytryptamine; D017294:Ondansetron