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N.A. Sharif, C.R. Kelly, J.Y. Crider, G.W. Williams, M.A. McLaughlin, A.P. Dantanaryana, P.A. Zinke, J.A. May; AL–34662: A Novel, Potent and Efficacious Ocular Hypotensive Serotonin–2 Receptor Agonist . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2944.
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© ARVO (1962-2015); The Authors (2016-present)
To study the molecular pharmacology of AL–34662 (1((S)–2aminopropyl)–1H–indazol–6–ol), a serotonin–2 (5HT2) receptor agonist that lowers interocular pressure (IOP).
Standard procedures were utilized to determine the receptor binding affinity, functional potency (using phosphoinositide (PI) hydrolysis and intracellular Ca2+ ([Ca2+]i) and in vivo IOP–lowering efficacy of AL–34662.
AL–34662 potently inhibited [125I]–DOI binding to rat and human brain 5HT2 receptors (IC50 = 0.8 – 1.6 nM) but exhibited relatively weak affinity (micromolar) for numerous other receptors, ion channels and transport sites. AL–34662 stimulated PI hydrolysis in human trabecular meshwork (h–TM) cells (EC50 = 254 ± 50 nM, n = 10), in human ciliary muscle (h–CM) cells (EC50 = 289 ± 80 nM, n = 7) and in rat vascular smooth muscle cells (A7r5) (EC50 = 105 ± 9 nM). AL–34662 also potently mobilized [Ca2+]i via 5HT2 receptors in rat A7r5 cells (EC50 = 43 ± 2 NM) and in h–TM cells (EC50 = 38 ± 8 nM, n = 6). Furthermore, AL–34662 was a potent agonist at the cloned human 5HT2A, 5HT2B and 5HT2C receptors (EC50s = 0.4 – 3.2 nM). PI hydrolysis induced by AL–34662 in rat A7r5 cells was antagonized by M–100907, a 5HT2A–receptor–selective antagonist (IC50 = 5 nM). AL–34662 efficaciously lowered IOP in concious ocular hypertensive cynomolgus monkey eyes (33 ± 3 % reduction [p < 0.001] 6 hr post–dosing with 300 µg; baseline IOP = 41.8 ± 3.8 mmHg).
AL–34662 is a novel and potent 5HT2 agonist that efficaciously lowers IOP in the concious ocular hypertensive monkey eyes. CR: E
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