1-((S)-2-Aminopropyl)-1H-indazol-6-ol:  A Potent Peripherally Acting 5-HT₂Receptor Agonist with Ocular Hypotensive Activity

Abstract

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.

Psychedelics

“…These effects were attributed to an increase in uveoscleral outflow, an important component of aqueous humor dynamics that contributes to the maintenance of IOP. May et al (2006) discovered indazole-based 5-HT 2A agonists with poor CNS activity and solution stability 332 Nichols superior to conventional tryptamine-based 5-HT 2 agonists such as serotonin and AMS. They identified one compound, 1-((S)-2-aminopropyl)-1H-indazol-6-ol), with an EC 50 of 43 nM and E max of 89% that lowered intraocular pressure by 33% in conscious ocular hypertensive monkeys.…”

Structure–activity relationships of serotonin 5‐HT2A agonists

“…11,12 In particular, AL-38022A 12 was developed as a highly potent 5-HT 2A agonist with effects against glaucoma ( Figure 8). It was a full agonist at all of the 5-HT2 receptor subtypes, with an EC50 in the range 0.5-2.2 nM for several functional responses.…”

Structure–Activity Relationships of Phenylalkylamines as Agonist Ligands for 5‐HT2A Receptors

“…[50] The reduction in IOP by 5-HT 2A agonists has recently been recognized as an efficient treatment for ocular hypertension and glaucoma. [18,51,52] Agonist activation of 5-HT 2A and 5-HT 2B receptors results in liver regeneration, [35] however clinical efficacy in liver regeneration following transplantation remains to be demonstrated. [53,54] 5-HT 2B receptor antagonists can be used to treat anxiety disorders, however, their application is limited because of the role this receptor plays in embryogenesis.…”