Published investigations of serotonin-1A (5-hydroxytryptamine 1A ; 5-HT 1A ) receptor agonists and serotonin-2A (5-hydroxytryptamine 2A ; 5-HT 2A ) receptor antagonists in nonprimate species provide conflicting results with regard to their intraocular pressurelowering efficacy. Thus, their therapeutic utility in the treatment of human glaucoma has been confusing. We evaluated the effect of selected 5-HT 1A agonists and 5-HT 2A receptor antagonists on intraocular pressure in a nonhuman primate model, the conscious cynomolgus monkey with laser-induced ocular hypertension. Neither selective 5-HT 1A agonists [e.g., R-8-hydroxy-2-(di-n-propylamino)tetralin and flesinoxan] nor selective 5-HT 2 receptor antagonists [e.g.,pressure in the primate model following topical ocular administration. However, compounds that function as agonists at both the 5-HT 1A and 5-HT 2 receptors were found to effectively lower intraocular pressure in the model: 5-hydroxy-␣-methyltryptamine, 5-methoxy-␣-methyltryptamine, 5-hydroxy-N,N-dimethyltryptamine (bufotenine), and 5-methoxy-N,N-dimethyltryptamine. Furthermore, the selective 5-HT 2 receptor agonist R-(Ϫ)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane lowered intraocular pressure in the primate model, demonstrating a pharmacological response associated with activation of the 5-HT 2 receptor. These observations suggest that compounds that function as efficient agonists at 5-HT 2 receptors should be considered as potential agents for the control of intraocular pressure in the treatment of ocular hypertension and glaucoma in humans.Identification of several of the numerous serotonin receptors in ocular tissues of the anterior segment of the eye, including the iris-ciliary body of rabbit (Chidlow et al., 1998) and human (Martin et al., 1992), suggests that this neurotransmitter may play an important role in the regulation of intraocular pressure (IOP). Serotonin (5-hydroxytryptamine; 5-HT) is also found in the aqueous humor of humans (Veglio et al., 1998) and other mammals (Boerrigter et al., 1992). These observations have generated considerable interest in the role that serotonin might have in aqueous humor dynamics and even whether 5-HT might be involved in the development of ocular hypertension and glaucoma. There have been numerous conflicting reports on the effect of 5-HT and various 5-HT receptor ligands on IOP in the rabbit, dog, and humans. These observed differences in IOP response may be due to species differences, route of administration, or the lack of 5-HT receptor selectivity of the agents evaluated. For example, 5-HT has been shown to lower IOP in rabbits following intravenous injection (Chiang, 1974). However, when injected intracamerally in the rabbit, a rise in IOP was observed (Krootila et al., 1987). Furthermore, topical ocular administration of 5-HT to the rabbit was reported to result in either a decrease (Krootila et al., 1987) or an increase (Meyer-Bothling et al., 1993) in IOP.Article, publication date, and citation information can be found at

Travoprost is the isopropyl ester prodrug of a high affinity, selective FP prostaglandin full receptor agonist. In contrast to travoprost acid's high affinity and efficacy at the FP receptor, there is only sub-micromolar affinity for the DP, EP1, EP3, EP4, IP, and TP receptors. Travoprost produced a lower incidence of ocular irritation than PGF20 isopropyl ester at a dose of 1 microg in the New Zealand albino (NZA) rabbit. Topical ocular application of travoprost produced a marked miotic effect in cats following doses of 0.01, 0.03 and 0.1 microg. In the ocular hypertensive monkey, b.i.d. application of 0.1 and 0.3 microg of travoprost afforded peak reduction in intraocular pressure (IOP) of 22.7% and 28.6%, respectively. Topical application of travoprost was well tolerated in rabbits, cats and monkeys, causing no ocular irritation or discomfort at doses up to 1 microg. Travoprost is a promising ocular hypotensive prostaglandin FP derivative that has the ocular hypotensive efficacy of PGF2alpha isopropyl ester but with less severe ocular side effects.

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Serotonin 5-HT(2) receptor agonists have been identified as a potential new class of agents for the treatment of ocular hypertension and glaucoma. The initially reported tryptamine analogues displayed either poor solution stability, potent central nervous system activity, or both of these undesirable characteristics and were unacceptable for clinical evaluation. A series of 1-(2-aminopropyl)-1H-indazole analogues was synthesized and evaluated for their suitability for consideration as clinical candidates. 1-((S)-2-Aminopropyl)-1H-indazol-6-ol (9) was identified as a peripherally acting potent 5-HT(2) receptor agonist (EC(50) = 42.7 nM, E(max) = 89%) with high selectivity for the 5-HT(2) receptors relative to other serotonergic receptor subtypes and other families of receptors and has significantly greater solution stability than alpha-methyl-5-hydroxytryptamine. Additionally, 9 potently lowers intraocular pressure in conscious ocular hypertensive monkeys (-13 mmHg, 33%); this reduction appears to be through a local rather than a centrally mediated effect. Compound 9 appears to be an excellent 5-HT(2) receptor agonist for conducting further studies directed toward a clinical proof-of-concept study for this class of ocular hypotensive agents.

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