title: A novel and selective 5-HT2 receptor agonist with ocular hypotensive activity: (S)-(+)-1-(2-aminopropyl)-8,9-dihydropyrano[3,2-e]indole.
abstract: Serotonin 5-HT2 receptor agonists have recently been shown to be effective in lowering intraocular pressure in nonhuman primates and represent a potential new class of antiglaucoma agents. As part of an effort to identify new selective agonists at this receptor, we have found that (S)-(+)-1-(2-aminopropyl)-8,9-dihydropyrano[3,2-e]indole (AL-37350A, 11) has high affinity and selectivity (>1000-fold) for the 5-HT(2) receptor relative to other 5-HT receptors. More specifically, 11 is a potent agonist at the 5-HT2A receptor (EC50 = 28.6 nM, E(max) = 103%) that is comparable to serotonin. Evaluation of 11 in conscious ocular hypertensive cynomolgus monkeys showed this compound to be efficacious in reducing intraocular pressure (13.1 mmHg, -37%). Thus, 11 is a potent full agonist with selectivity for the 5-HT2 receptor and is anticipated to serve as a useful tool in exploring the role of the 5-HT2 receptor and its effector system in controlling intraocular pressure.
authors.affiliation: Medicinal Chemistry Department, Ophthalmic Products Research, Alcon Research, Ltd., 6201 South Freeway, Fort Worth, Texas 76134, USA. jesse.may@alconlabs.com
authors.forename: Jesse A
authors.initials: JA
authors.lastname: May
authors.forename: Hwang-Hsing
authors.initials: HH
authors.lastname: Chen
authors.forename: Andrew
authors.initials: A
authors.lastname: Rusinko
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Lynch
authors.forename: Najam A
authors.initials: NA
authors.lastname: Sharif
authors.forename: Marsha A
authors.initials: MA
authors.lastname: McLaughlin
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry* / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008252:Macaca fascicularis; D008958:Models, Molecular; D009798:Ocular Hypertension / Q000188:drug therapy*; D011869:Radioligand Assay; D051381:Rats; D011941:Receptors, Adrenergic / Q000378:metabolism; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism
chemical_list: C478566:1-(2-aminopropyl)-8,9-dihydropyrano(3,2-e)indole; D000959:Antihypertensive Agents; D007211:Indoles; D011941:Receptors, Adrenergic; D011985:Receptors, Serotonin; D011994:Recombinant Proteins; D017366:Serotonin Receptor Agonists