Flesinoxan, a 5-HT1A receptor agonist/alpha 1-adrenoceptor antagonist, lowers intraocular pressure in NZW rabbits

Curr Eye Res. 2001 Aug;23(2):144-53. doi: 10.1076/ceyr.23.2.144.5480.

Abstract

Purpose: alpha1-Adrenoceptor antagonists and 5-HT1A receptor agonists reduce intraocular pressure (IOP) in the rabbit. The aims of this study were firstly, to determine the IOP-lowering effects of flesinoxan and selected other hybrid 5-HT1A receptor agonists/alpha1-adrenoceptor antagonists, and secondly, to investigate the mechanism of action of the IOP response to flesinoxan.

Methods: IOP and total outflow facility were measured in rabbits after administration of hybrid drugs. Inositol phosphates accumulation assays were performed using standard methodologies.

Results: Topical unilateral instillation of the drugs caused dose-related reductions of IOP. Comparison of the compounds tested revealed a potency order of WB 4101 > flesinoxan > 5-methyl-urapidil > or = BMY7378 > urapidil. WB-4101 caused a small increase in total outflow facility whereas flesinoxan had no effect. Measurement of the IC50 values for inhibition of phenylephrine-stimulated inositol phosphates accumulation in rabbit iris-ciliary body revealed a potency order of WB 4101 > 5-methyl-urapidil > flesinoxan > BMY 7378 = urapidil. Topical flesinoxan was ineffective in reversing phenylephrine-induced mydriasis, yet, pretreatment with the 5-HT1A receptor antagonists MDL 73005EF and pindolol only partially blocked the hypotensive effect of topical flesinoxan.

Conclusions: The present studies indicate the potent and efficacious IOP-lowering capabilities of flesinoxan and certain other ligands with affinity for 5-HT1A receptors/alpha1-adrenoceptors. The exact mechanisms by which these drugs lower IOP in the rabbit are complex but our results indicate that flesinoxan likely reduces aqueous secretion.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-1 Receptor Antagonists*
  • Animals
  • Aqueous Humor / metabolism
  • Ciliary Body / drug effects
  • Ciliary Body / metabolism
  • Female
  • Inositol Phosphates / biosynthesis
  • Intraocular Pressure / drug effects*
  • Male
  • Piperazines / pharmacology*
  • Pupil / drug effects
  • Rabbits
  • Receptors, Serotonin / metabolism*
  • Receptors, Serotonin, 5-HT1
  • Serotonin Receptor Agonists / pharmacology*

Substances

  • Adrenergic alpha-1 Receptor Antagonists
  • Inositol Phosphates
  • Piperazines
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT1
  • Serotonin Receptor Agonists
  • flesinoxan