A pharmacological profile of the selective silent 5-HT1A receptor antagonist, WAY-100635

• Published in: European journal of pharmacology 1995-07, Vol.281 (1), p.81-88
• Main Authors: Forster, E A, Cliffe, I A, Bill, D J, Dover, G M, Jones, D, Reilly, Y, Fletcher, A
• Format: Article
• Language: English
• Subjects: 8-Hydroxy-2-(di-n-propylamino)tetralin - antagonists & inhibitors; 8-Hydroxy-2-(di-n-propylamino)tetralin - pharmacology; Animals; Behavior, Animal - drug effects; Binding Sites; Body Temperature - drug effects; Female; Guinea Pigs; Hypothermia - chemically induced; Ileum - drug effects; Ileum - physiology; In Vitro Techniques; Male; Mice; Neurons - drug effects; Neurons - physiology; Piperazines - metabolism; Piperazines - pharmacology; Pyridines - metabolism; Pyridines - pharmacology; Radioligand Assay; Raphe Nuclei - drug effects; Raphe Nuclei - physiology; Rats; Rats, Sprague-Dawley; Serotonin - physiology; Serotonin Antagonists - metabolism; Serotonin Antagonists - pharmacology
• ISSN: 0014-2999
• DOI: 10.1016/0014-2999(95)00234-c

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.