Nelotanserin，一种新型的选择性人类5-羟色胺2A反向激动剂，用于治疗失眠。,Journal of Pharmacology and Experimental Therapeutics

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Nelotanserin，一种新型的选择性人类5-羟色胺2A反向激动剂，用于治疗失眠。
Journal of Pharmacology and Experimental Therapeutics ( IF 3.1 ) Pub Date : 2009-10-21 , DOI: 10.1124/jpet.109.160994
Hussien A Al-Shamma ₁ , Christen Anderson , Emil Chuang , Remy Luthringer , Andrew J Grottick , Erin Hauser , Michael Morgan , William Shanahan , Bradley R Teegarden , William J Thomsen , Dominic Behan

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5-羟色胺（5-HT）（2A）受体反向激动剂是治疗睡眠维持性失眠的有前途的治疗剂。在这些药物中有Nelotanserin，一种有效的选择性5-HT（2A）反向激动剂。放射性配体结合和功能性肌醇磷酸盐积累测定均表明，尼洛坦丝林对5-HT（2A）受体的纳摩尔浓度低，与5-HT（2C）和5-HT（2B）相比具有至少30倍和5000倍的选择性受体。Nelotanserin口服预防（+/-）-1-（2,5-二甲氧基-4-碘苯基）-2-氨基丙烷（DOI; 5-HT（2A）激动剂）引起的运动不足，睡眠巩固增加和总非快速增加眼动睡眠时间和深度睡眠，后者的特征是脑电图（EEG）三角洲能力的增强。重复亚慢性给药后，这些对大鼠睡眠的影响得以维持。在健康的人类志愿者中，口服给药后，Nelotanserin迅速吸收，并在1小时后达到最大浓度。服药后2至4小时内发生脑电图，并与警惕性降低相一致。在健康受试者的午睡后失眠模型中评估了神经硫蛋白的剂量反应。所有剂量（最多40毫克）的神经节苷脂均能显着改善睡眠巩固措施，包括减少阶段转移次数，降低睡眠开始后的清醒次数，微觉指数和睡眠发作次数，以及增加睡眠发作持续时间。Nelotanserin不会影响总睡眠时间或睡眠发作潜伏期。此外，服药后早晨观察到的主观药效学作用微乎其微，对精神运动技能或记忆没有功能性影响。这些研究表明，神经节苷脂的功效和安全性可能非常适合治疗睡眠维持性失眠。

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Nelotanserin, a novel selective human 5-hydroxytryptamine2A inverse agonist for the treatment of insomnia.

5-Hydroxytryptamine (5-HT)(2A) receptor inverse agonists are promising therapeutic agents for the treatment of sleep maintenance insomnias. Among these agents is nelotanserin, a potent, selective 5-HT(2A) inverse agonist. Both radioligand binding and functional inositol phosphate accumulation assays suggest that nelotanserin has low nanomolar potency on the 5-HT(2A) receptor with at least 30- and 5000-fold selectivity compared with 5-HT(2C) and 5-HT(2B) receptors, respectively. Nelotanserin dosed orally prevented (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 5-HT(2A) agonist)-induced hypolocomotion, increased sleep consolidation, and increased total nonrapid eye movement sleep time and deep sleep, the latter marked by increases in electroencephalogram (EEG) delta power. These effects on rat sleep were maintained after repeated subchronic dosing. In healthy human volunteers, nelotanserin was rapidly absorbed after oral administration and achieved maximum concentrations 1 h later. EEG effects occurred within 2 to 4 h after dosing, and were consistent with vigilance-lowering. A dose response of nelotanserin was assessed in a postnap insomnia model in healthy subjects. All doses (up to 40 mg) of nelotanserin significantly improved measures of sleep consolidation, including decreases in the number of stage shifts, number of awakenings after sleep onset, microarousal index, and number of sleep bouts, concomitant with increases in sleep bout duration. Nelotanserin did not affect total sleep time, or sleep onset latency. Furthermore, subjective pharmacodynamic effects observed the morning after dosing were minimal and had no functional consequences on psychomotor skills or memory. These studies point to an efficacy and safety profile for nelotanserin that might be ideally suited for the treatment of sleep maintenance insomnias.

更新日期：2019-11-01

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