May 2006
Volume 47, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2006
AL–34662: A Novel, Potent and Efficacious Ocular Hypotensive Serotonin–2 Receptor Agonist
Author Affiliations & Notes
  • N.A. Sharif
    Alcon Research, Ltd., Fort Worth, TX
  • C.R. Kelly
    Alcon Research, Ltd., Fort Worth, TX
  • J.Y. Crider
    Alcon Research, Ltd., Fort Worth, TX
  • G.W. Williams
    Alcon Research, Ltd., Fort Worth, TX
  • M.A. McLaughlin
    Alcon Research, Ltd., Fort Worth, TX
  • A.P. Dantanaryana
    Alcon Research, Ltd., Fort Worth, TX
  • P.A. Zinke
    Alcon Research, Ltd., Fort Worth, TX
  • J.A. May
    Alcon Research, Ltd., Fort Worth, TX
  • Footnotes
    Commercial Relationships  N.A. Sharif, Alcon Research, Ltd., E; C.R. Kelly, Alcon Research, Ltd., E; J.Y. Crider, Alcon Research, Ltd., E; G.W. Williams, Alcon Research, Ltd., E; M.A. McLaughlin, Alcon Research, Ltd., E; A.P. Dantanaryana, Alcon Research, Ltd., E; P.A. Zinke, Alcon Research, Ltd., E; J.A. May, Alcon Research, Ltd., E.
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science May 2006, Vol.47, 2944. doi:
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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)

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Abstract

Purpose: : 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).

Methods: : 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.

Results: : 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).

Conclusions: : AL–34662 is a novel and potent 5HT2 agonist that efficaciously lowers IOP in the concious ocular hypertensive monkey eyes. CR: E

Keywords: pharmacology • receptors: pharmacology/physiology • signal transduction: pharmacology/physiology 
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