Ocular Hypotension: Involvement of Serotonergic 5-HT2 Receptors

Abstract

AbstractSerotonergic nerves innervate various parts of the eye, including the ciliary body, and serotonin (5-hydroxytryptamine, or 5-HT) has been found in the aqueous humor in the anterior chamber of animal and human eyes. 5-HT2A-C receptor mRNAs are present in human ocular tissues involved in modulation of intraocular pressure (IOP) including ciliary body (5-HT2A > 5-HT2B > 5-HT2C), ciliary epithelium (5-HT2A > 5-HT2B = 5-HT2C), and trabecular meshwork (TM) (5-HT2A = 5-HT2B > > 5-HT2C), and quantitative autoradiographic studies revealed relatively high specific binding of [3H]5-HT and [3H]ketanserin to human ciliary epithelium and longitudinal ciliary muscle (CM). 5-HT2A receptors stimulated phosphoinositide (PI) hydrolysis and mobilized intracellular Ca2+ in isolated human CM and TM cells when exposed to 5-HT2A-C receptor agonists (e.g., (R)-DOI, α-methyl-5-HT, MK-212, mCPP, BW-723C86, cabergoline, AL-34662), and these responses were blocked by selective antagonists (e.g., M-100970).Extensive IOP-measurement studies in rabbits, cats, monkeys, and rats revealed major species differences in mediation of ocular hypotension in response to numerous 5-HT2 receptor-selective agonists and antagonists. While rabbit IOPs were decreased by 5-HT1A agonists, these compounds failed to influence monkey IOP. However, while 5-HT2 agonists caused significant IOP reductions in monkeys and rats, these compounds were inactive in rabbits and cats. Further studies indicated a strong involvement of 5-HT2A receptors in mediating IOP lowering in conscious ocular hypertensive cynomolgus monkeys, although due to the relative nonselectivity of some compounds tested, it appeared 5-HT2C receptor activation may be partially responsible for lowering IOP in the nonhuman primates. Extensive structure-activity studies resulted in the discovery of AL-34662 as a peripherally acting selective 5-HT2 agonist (relative to other 5-HT receptor families) with significant affinity, potency, and efficacy at 5-HT2A, 5-HT2B, and 5-HT2C receptors. AL-34662 lowered IOP (33 ± 3% at 300 μg topical ocular dose) out to 6 h after a single topical ocular dose in the conscious ocular hypertensive cynomolgus monkeys. Such agents represent potentially novel ocular hypotensive drugs of the future for the treatment of elevated IOP and glaucoma.KeywordsAqueous HumorOcular HypertensionCiliary BodyTrabecular MeshworkCiliary EpitheliumThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.