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(2)

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Abstract #17529 Published in IGR 9-2

AL-34662: A potent, selective, and efficacious ocular hypotensive serotonin-2 receptor agonist

Sharif NA; McLaughlin MA; Kelly CR
Journal of Ocular Pharmacology and Therapeutics 2007; 23: 1-13

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Purpose and METHODS: The aim of this study was to determine the ocular pharmacological characteristics of AL-34662 (1-((S)-2-aminopropyl)-1H-indazole- 6-ol), a new synthetic serotonin-2 (5-HT₂) receptor-agonist ocular hypotensive agent. A variety of well-documented in vitro and in vivo procedures were utilized to study the pharmacological attributes of AL-34662. RESULTS: AL-34662 exhibited a high affinity for the rat and human 5-HT(2) receptor (IC₅₀ = 0.8-1.5 nM) and for cloned human-5-HT_2A-C) receptors (IC₅₀ = 3-14.5 nM). AL-34662 stimulated phosphoinositide turnover in human ciliary muscle (h-CM; EC⁵⁰ = 289 ± 80 nM) and in human trabecular meshwork (h-TM; EC⁵⁰ = 254 ± 50 nM) cells. AL-34662 also mobilized intracellular Ca²⁺ ([Ca ²⁺]_i) in h-CM (EC⁵⁰ = 140 ± 23 nM) and h-TM (EC⁵⁰ = 38 ± 8 nM) cells, being a full agonist like 5-HT itself. AL-34662's effects in the h-CM (and h-TM) cells were potently antagonized by 5-HT(_2A)-antagonist M-100907. (IC₅₀ = 1.8 ± 0.7 nM), but weakly by 5-HT(_2B)-antagonist (RS-127445 IC (50) > 10 μM), 5-HT(2B/C)- antagonist (SB-242084 IC₅₀ = 2.08 μM) and 5-HT_2C antagonist (RS-102221 IC (50) > 1 μM). AL-34662 caused relatively minimal ocular discomfort and hyperemia in rabbit and guinea pig eyes. It efficaciously lowered intraocular pressure (IOP) in the conscious ocular hypertensive monkey eyes (33% at 300 μg). The (R)-enantiomer (AL-34707) and the racemate (AL-34497) were less potent and/or efficacious than AL-34662 in all of these assays. CONCLUSIONS: AL-34662 is a high-affinity 5-HT(2) receptor agonist that potently mobilizes [Ca²⁺]_i in h-CM and h-TM cells, and which efficaciously lowers IOP in conscious ocular hypertensive cynomolgus monkey eyes through a local effect with minimal side-effects.

Dr. N.A. Sharif, Alcon Research, Ltd., 6201 South Freeway, Fort Worth, TX 76134, USA. Naj.Sharif@Alconlabs.com

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Classification:

11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)

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