title: A pharmacological profile of the selective silent 5-HT1A receptor antagonist, WAY-100635.
abstract: WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2- pyridinyl)cyclohexanecarboxamide trihydrochloride) is an achiral phenylpiperazine derivative that binds with high affinity and selectivity to the 5-HT1A receptor. WAY-100635 displaced specific binding of the 5-HT1A radioligand, [3H]8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), to rat hippocampal membranes with a pIC50 of 8.87. This represented a greater than 100-fold selectivity relative to binding at other 5-HT receptor subtypes and major neurotransmitter receptor, reuptake and ion channel sites. In functional assays, WAY-100635 was a potent 5-HT1A receptor antagonist, with no evidence of any 5-HT1A receptor agonist or partial agonist activity. In the isolated guinea-pig ileum WAY-100635 was a potent and, at high concentrations, an insurmountable antagonist of the 5-HT1A receptor agonist action of 5-carboxamidotryptamine, with an apparent pA2 value (at 0.3 nM) of 9.71. WAY-100635 blocked the inhibitory action of 8-OH-DPAT on dorsal raphe neuronal firing in the anaesthetised rat at doses which had no inhibitory action per se. In behavioural models, WAY-100635 itself induced no overt behavioural changes but potently antagonised the behavioural syndrome induced by 8-OH-DPAT in the rat and guinea-pig (minimum effective dose = 0.003 mg/kg s.c. and ID50 = 0.01 mg/kg s.c., respectively). WAY-100635 also blocked the hypothermia induced by 8-OH-DPAT in the mouse and rat with ID50 values of 0.01 mg/kg s.c. These data indicate that WAY-100635 will be used as a standard antagonist in further studies of 5-HT1A receptor function.
authors.affiliation: Department of Neuropharmacology, Wyeth Research (UK) Ltd., Maidenhead, Berkshire.
authors.forename: E A
authors.initials: EA
authors.lastname: Forster
authors.forename: I A
authors.initials: IA
authors.lastname: Cliffe
authors.forename: D J
authors.initials: DJ
authors.lastname: Bill
authors.forename: G M
authors.initials: GM
authors.lastname: Dover
authors.forename: D
authors.initials: D
authors.lastname: Jones
authors.forename: Y
authors.initials: Y
authors.lastname: Reilly
authors.forename: A
authors.initials: A
authors.lastname: Fletcher
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001665:Binding Sites; D001831:Body Temperature / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D007035:Hypothermia / Q000139:chemically induced; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology*; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D011903:Raphe Nuclei / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000502:physiology; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D010879:Piperazines; D011725:Pyridines; D012702:Serotonin Antagonists; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin