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

Eur J Pharmacol. 1995 Jul 25;281(1):81-8. 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.

MeSH terms

  • 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*


  • Piperazines
  • Pyridines
  • Serotonin Antagonists
  • Serotonin
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
  • 8-Hydroxy-2-(di-n-propylamino)tetralin