Flesinoxan, a 5-HT1A receptor agonist/alpha 1-adrenoceptor antagonist, lowers intraocular pressure in NZW rabbits.
OBJECTIVE
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.
Chidlow
G
G
Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, UK.
Cupido
A
A
Melena
J
J
Osborne
N N
NN
D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism; D002924:Ciliary Body / Q000187:drug effects / Q000378:metabolism; D005260:Female; D007295:Inositol Phosphates / Q000096:biosynthesis; D007429:Intraocular Pressure / Q000187:drug effects*; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D011680:Pupil / Q000187:drug effects; D011817:Rabbits; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D058668:Adrenergic alpha-1 Receptor Antagonists; D007295:Inositol Phosphates; D010879:Piperazines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; C056895:flesinoxan