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-HT2 receptor (IC50 = 0.8–1.5 nM) and for cloned human 5-HT2A-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+ ([Ca2+]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-HT2A-antagonist M-100907 (IC50 = 1.8 ± 0.7 nM), but weakly by 5-HT2B-antagonist (RS-127445 IC50 > 10 μM), 5-HT2B/C- antagonist (SB-242084 IC50 = 2.08 μM) and 5-HT2C antagonist (RS-102221 IC50 > 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-HT2 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.
