title: AL-34662: a potent, selective, and efficacious ocular hypotensive serotonin-2 receptor agonist.
abstract: OBJECTIVE
  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.affiliation: Ophthalmology Discovery Research, Alcon Research, Ltd., Fort Worth, TX 76134, USA. Naj.Sharif@Alconlabs.com
authors.forename: Najam A
authors.initials: NA
authors.lastname: Sharif
authors.forename: Marsha A
authors.initials: MA
authors.lastname: McLaughlin
authors.forename: Curtis R
authors.initials: CR
authors.lastname: Kelly
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000633:toxicity; D016466:CHO Cells / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002924:Ciliary Body / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D006940:Hyperemia / Q000139:chemically induced; D007191:Indazoles / Q000737:chemistry / Q000494:pharmacology*; D007429:Intraocular Pressure / Q000187:drug effects*; D008024:Ligands; D008252:Macaca fascicularis; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D015814:Ocular Hypotension / Q000188:drug therapy*; D010716:Phosphatidylinositols / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D058826:Serotonin 5-HT2 Receptor Agonists; D014129:Trabecular Meshwork / Q000187:drug effects / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
chemical_list: C520575:1-(2-aminopropyl)-1H-indazole-6-ol; D000959:Antihypertensive Agents; D007191:Indazoles; D008024:Ligands; D010716:Phosphatidylinositols; D058826:Serotonin 5-HT2 Receptor Agonists; D002118:Calcium