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

Abstract

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 microM), 5-HT2B/C- antagonist (SB-242084 IC50=2.08 microM) and 5-HT2C antagonist (RS-102221 IC50>1 microM). 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 microg). 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.

• Authors: Najam A Sharif, Marsha A McLaughlin, Curtis R Kelly
• Journal: Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics (J Ocul Pharmacol Ther) Vol. 23 Issue 1 Pg. 1-13 (Feb 2007) ISSN: 1080-7683 [Print] United States
• PMID: 17341144 (Publication Type: Journal Article)

Chemical References

• 1-(2-aminopropyl)-1H-indazole-6-ol
• Antihypertensive Agents
• Indazoles
• Ligands
• Phosphatidylinositols
• Serotonin 5-HT2 Receptor Agonists
• Calcium

Topics

• Animals
• Antihypertensive Agents (pharmacology, toxicity)
• CHO Cells (drug effects)
• Calcium (metabolism)
• Cells, Cultured
• Ciliary Body (drug effects, metabolism)
• Cricetinae
• Cricetulus
• Drug Evaluation, Preclinical
• Female
• Guinea Pigs
• Humans
• Hyperemia (chemically induced)
• Indazoles (chemistry, pharmacology)
• Intraocular Pressure (drug effects)
• Ligands
• Macaca fascicularis
• Muscle, Smooth (drug effects, metabolism)
• Ocular Hypotension (drug therapy)
• Phosphatidylinositols (metabolism)
• Rabbits
• Rats
• Serotonin 5-HT2 Receptor Agonists
• Trabecular Meshwork (drug effects, metabolism)
• Vasodilation (drug effects)