Biochemical and Pharmacological Properties of SR 46349B, a New Potent and Selective 5-hydroxytryptamine2 Receptor Antagonist

J Pharmacol Exp Ther. 1992 Aug;262(2):759-68.

Abstract

A new potent, selective and p.o. active serotonergic [5-hydroxytryptamine (5-HT2)] receptor antagonist, SR 46349B [trans, 4-([3Z)3-(2-dimethylaminoethyl)oxyimino-3(2-flurophenyl++ +)propen-1-yl]phenol hemifumarate) has been characterized by a series of "in vitro" and "in vivo" methods. Based upon binding studies with 5-HT2 receptors in rat brain cortical membranes and blockade of 5-HT-induced contractions in isolated tissues (rabbit thoracic aorta, rat jugular vein, rat caudal artery, rat uterus and guinea pig trachea), SR 46349B showed high affinity for 5-HT2 receptors. Furthermore, SR 46349B displayed moderate affinity for the 5-HT1C receptor and had no affinity for the other 5-HT1 subclass (5-HT1A, 5-HT1B or 5-HT1D), dopamine (D1 or D2), "alpha" adrenergic (alpha-1 or alpha-2), sodium and calcium channel and histamine (H1) receptors. It did not interact with histamine (H1), alpha-1 adrenergic and 5-HT3 receptors in smooth muscle preparations. No inhibition of the uptake of norepinephrine, dopamine or 5-HT was seen. Based upon blockade of pressor responses to 5-HT in pithed rats and in vivo binding studies in mice, SR 46349B was found to be a potent and p.o. active 5-HT2 receptor antagonist with a relatively long duration of action. Behavioral experiments, including mescaline- and 5-hydroxytryptophan-induced head twitches and learned helplessness, as well as sleep-waking cycle and EEG spectral parameter studies, indicated that SR 46349B has a classical 5-HT2 psychopharmacological antagonist profile.

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Electroencephalography
  • Escape Reaction / drug effects
  • Female
  • Fluorobenzenes / pharmacology*
  • Guinea Pigs
  • In Vitro Techniques
  • Ketanserin / metabolism
  • Male
  • Muscle Contraction / drug effects
  • Phenols / pharmacology*
  • Rats
  • Rats, Inbred Strains
  • Receptors, Serotonin / metabolism
  • Serotonin Antagonists* / metabolism
  • Serotonin Antagonists* / pharmacology*
  • Sleep / drug effects

Substances

  • Fluorobenzenes
  • Phenols
  • Receptors, Serotonin
  • Serotonin Antagonists
  • SR 46349B
  • Ketanserin