Arena Pharmaceuticals, Inc, 6166 Nancy Ridge Drive, San Diego, California 92121, USA.
J Med Chem. 2010 Mar 11;53(5):1923-36. doi: 10.1021/jm9007328.
Insomnia affects a growing portion of the adult population in the U.S. Most current therapeutic approaches to insomnia primarily address sleep onset latency. Through the 5-hydroxytryptamine(2A) (5-HT(2A)) receptor, serotonin (5-HT) plays a role in the regulation of sleep architecture, and antagonists/inverse-agonists of 5-HT(2A) have been shown to enhance slow wave sleep (SWS). We describe here a series of 5-HT(2A) inverse-agonists that when dosed in rats, both consolidate the stages of NREM sleep, resulting in fewer awakenings, and increase a physiological measure of sleep intensity. These studies resulted in the discovery of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl]-3-(2,4-difluorophenyl)urea (Nelotanserin), a potent inverse-agonist of 5-HT(2A) that was advanced into clinical trials for the treatment of insomnia.
失眠影响了越来越多的美国成年人。目前治疗失眠的主要方法主要针对入睡潜伏期。通过 5-羟色胺（2A）（5-HT（2A））受体，5-羟色胺（5-HT）在调节睡眠结构中起作用，并且 5-HT（2A）的拮抗剂/反向激动剂已被证明可增强慢波睡眠（SWS）。在这里，我们描述了一系列 5-HT（2A）反向激动剂，当在大鼠中给药时，它们都巩固了非快速眼动（NREM）睡眠的阶段，导致更少的觉醒，并增加了睡眠强度的生理测量。这些研究导致发现了 1-[3-(4-溴-2-甲基-2H-吡唑-3-基）-4-甲氧基苯基]-3-(2,4-二氟苯基）脲（奈洛坦色林），这是一种有效的 5-HT（2A）反向激动剂，已进入失眠治疗的临床试验。
