title: WAY100135: a novel, selective antagonist at presynaptic and postsynaptic 5-HT1A receptors.
abstract: The novel phenylpiperazine derivative, (+/-)-WAY100135 (N-tert-butyl-3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylpro pionamide dihydrochloride), is a selective antagonist at both somatodendritic and postsynaptic 5-HT1A receptors. The IC50 of (+/-)-WAY100135 at the rat hippocampal 5-HT1A receptor was 34 nM, whereas its IC50 at a range of other receptor sites was > 2 microM. Up to a dose of 2.5 mg/kg i.v. (+/-)-WAY100135 induced a maximum 30% inhibition of raphe neuronal firing and (at 0.5 mg/kg i.v.) antagonised the inhibition of firing induced by 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) in anaesthetised rats. (+/-)-WAY100135 antagonised the action of 5-carboxamidoiodotryptamine in the guinea-pig ileum, with a pA2 of 7.2. (+/-)-WAY100135 had no agonist-like behavioural effects but antagonised the behavioural syndrome and hypothermia induced by 8-OH-DPAT in the rat and mouse, respectively. The interaction of (+/-)-WAY100135 with the 5-HT1A receptor was stereoselective; the (+)-enantiomer being markedly more active in binding, functional and behavioural studies. These data indicate that (+/-)-WAY100135 is the first highly selective antagonist at both somatodendritic and postsynaptic 5-HT1A receptors.
authors.affiliation: Department of Biomedical Research, Wyeth Research Ltd., Berkshire, UK.
authors.forename: A
authors.initials: A
authors.lastname: Fletcher
authors.forename: D J
authors.initials: DJ
authors.lastname: Bill
authors.forename: S J
authors.initials: SJ
authors.lastname: Bill
authors.forename: I A
authors.initials: IA
authors.lastname: Cliffe
authors.forename: G M
authors.initials: GM
authors.lastname: Dover
authors.forename: E A
authors.initials: EA
authors.lastname: Forster
authors.forename: J T
authors.initials: JT
authors.lastname: Haskins
authors.forename: D
authors.initials: D
authors.lastname: Jones
authors.forename: H L
authors.initials: HL
authors.lastname: Mansell
authors.forename: Y
authors.initials: Y
authors.lastname: Reilly
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000037:antagonists & inhibitors; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004594:Electrophysiology; D005260:Female; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007035:Hypothermia / Q000139:chemically induced / Q000188:drug therapy; D007082:Ileum / Q000187:drug effects; D008297:Male; D051379:Mice; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011869:Radioligand Assay; D011903:Raphe Nuclei / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D012702:Serotonin Antagonists; D013237:Stereoisomerism
chemical_list: D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C081293:WAY 100135; D012701:Serotonin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C047087:5-carboxamidotryptamine