Serotonin antagonists for use as antiglaucoma agents and their ocular penetration

Abstract

A previously unrecognized pharmacophore, 1-phenylpiperidine, has been found to lower intraocular pressure 25–30% in the recovery rate rabbit model. The compounds studied were piperidine, piperazine, morpholine and diethylamide derivatives. In a bioreceptor screening assay, 1-phenylpiperidine was classified as a serotonergic ligand, which based upon its IOP activity, is believed to be a serotonin antagonist. Physicochemical measurements were determined for selected derivatives which were also measured for excised corneal, scleral and conjunctival permeability. Penetration to various ocular tissues was determined after applying a constant concentration of derivative to either corneal or conjunctival/scleral routes of administration. Solutions of selected derivatives were applied with the use of a cylindrical well affixed to the cornea of an anesthetized white rabbit. After 2 h, concentrations of derivative were measured in cornea, aqueous humor, conjunctiva/sclera, iris/ciliary body and lens. For the derivatives tested, the more lipophilic compounds attained a higher permeability coefficient for either the cornea, sclera or conjunctiva. The more lipophilic derivatives also distributed in higher concentrations to cornea, aqueous humor, sclera/conjunctiva and lens, but not necessarily to iris/ciliary body, particularly when administered by the conjunctival/scleral route. The addition of certain functionalities to piperidine or piperazine ring structures significantly affected, confirmed by Costagliola et al. [4], but disputed by Mallorga and Sugrue [2].