May Jesse A, Chen Hwang-Hsing, Rusinko Andrew, Lynch Vincent M, Sharif Najam A, McLaughlin Marsha A
Medicinal Chemistry Department, Ophthalmic Products Research, Alcon Research, Ltd., 6201 South Freeway, Fort Worth, Texas 76134, USA.
J Med Chem. 2003 Sep 11;46(19):4188-95. doi: 10.1021/jm030205t.
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.
血清素5-HT2受体激动剂最近已被证明可有效降低非人类灵长类动物的眼压，代表了一类潜在的新型抗青光眼药物。作为识别该受体新选择性激动剂工作的一部分，我们发现(S)-(+)-1-(2-氨基丙基)-8,9-二氢吡喃并[3,2-e]吲哚(AL-37350A, 11)相对于其他5-HT受体，对5-HT(2)受体具有高亲和力和选择性(>1000倍)。更具体地说，11是5-HT2A受体的强效激动剂(EC50 = 28.6 nM, E(max) = 103%)，与血清素相当。在清醒的高眼压食蟹猴中对11进行评估，结果显示该化合物在降低眼压方面有效(13.1 mmHg, -37%)。因此，11是一种对5-HT2受体具有选择性的强效完全激动剂，预计将作为探索5-HT2受体及其效应系统在控制眼压中的作用的有用工具。
