索里昂（JZP-110）的神经化学和行为效应的特征：一种选择性多巴胺和去甲肾上腺素再摄取抑制剂。
Characterization of the Neurochemical and Behavioral Effects of Solriamfetol (JZP-110), a Selective Dopamine and Norepinephrine Reuptake Inhibitor.
机构信息
Jazz Pharmaceuticals, Palo Alto, California (M.G.B., D.L.H., L.P.C.); Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas (M.J.F., M.B.G.); Departments of Pharmacology and Neurology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania (R.B.M.); University of Arkansas for Medical Sciences, Little Rock, Arkansas (L.P.C.); Research and Development Service, Veterans Affairs Portland Health Care System, Portland, Oregon (A.J.); and Departments of Psychiatry and Behavioral Neuroscience, and Methamphetamine Abuse Research Center, Oregon Health and Science University, Portland, Oregon (A.J.)
Jazz Pharmaceuticals, Palo Alto, California (M.G.B., D.L.H., L.P.C.); Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas (M.J.F., M.B.G.); Departments of Pharmacology and Neurology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania (R.B.M.); University of Arkansas for Medical Sciences, Little Rock, Arkansas (L.P.C.); Research and Development Service, Veterans Affairs Portland Health Care System, Portland, Oregon (A.J.); and Departments of Psychiatry and Behavioral Neuroscience, and Methamphetamine Abuse Research Center, Oregon Health and Science University, Portland, Oregon (A.J.).
出版信息
J Pharmacol Exp Ther. 2018 Aug;366(2):367-376. doi: 10.1124/jpet.118.248120. Epub 2018 Jun 11.
Excessive sleepiness (ES) is associated with several sleep disorders, including narcolepsy and obstructive sleep apnea (OSA). A role for monoaminergic systems in treating these conditions is highlighted by the clinical use of US Food and Drug Administration-approved drugs that act on these systems, such as dextroamphetamine, methylphenidate, modafinil, and armodafinil. Solriamfetol (JZP-110) is a wake-promoting agent that is currently being evaluated to treat ES in patients with narcolepsy or OSA. Clinical and preclinical data suggest that the wake-promoting effects of solriamfetol differ from medications such as modafinil and amphetamine. The goal of the current studies was to characterize the mechanism of action of solriamfetol at monoamine transporters using in vitro and in vivo assays. Results indicate that solriamfetol has dual reuptake inhibition activity at dopamine (DA; IC = 2.9 M) and norepinephrine (NE; IC = 4.4 M) transporters, and this activity is associated in vivo with increased extracellular concentration of DA and NE as measured by microdialysis. Solriamfetol has negligible functional activity at the serotonin transporter (IC > 100 M). Moreover, the wake-promoting effects of solriamfetol are probably owing to activity at DA and NE transporters rather than other neurotransmitter systems, such as histamine or orexin. The dual activity of solriamfetol at DA and NE transporters and the lack of significant monoamine-releasing properties of solriamfetol might explain the differences in the in vivo effects of solriamfetol compared with modafinil or amphetamine. Taken together, these data suggest that solriamfetol may offer an important advancement in the treatment of ES in patients with narcolepsy or OSA.
过度嗜睡（ES）与几种睡眠障碍有关，包括嗜睡症和阻塞性睡眠呼吸暂停（OSA）。这些病症的治疗中，单胺能系统的作用已得到美国食品和药物管理局批准的作用于这些系统的药物的临床应用所强调，如右旋苯丙胺、哌甲酯、莫达非尼和阿莫达非尼。索里昂（JZP-110）是一种促醒剂，目前正在评估其治疗嗜睡症或 OSA 患者 ES 的疗效。临床前和临床数据表明，索里昂的促醒作用与莫达非尼和安非他命等药物不同。目前这些研究的目的是使用体外和体内测定法来确定索里昂对单胺转运体的作用机制。结果表明，索里昂对多巴胺（DA；IC = 2.9 M）和去甲肾上腺素（NE；IC = 4.4 M）转运体具有双重再摄取抑制活性，这种活性与通过微透析测量的 DA 和 NE 细胞外浓度的增加有关。索里昂对 5-羟色胺转运体（IC>100 M）几乎没有功能活性。此外，索里昂的促醒作用可能归因于对 DA 和 NE 转运体的活性，而不是其他神经递质系统，如组胺或食欲素。索里昂对 DA 和 NE 转运体的双重活性以及索里昂对单胺类递质无明显释放特性可能解释了与莫达非尼或安非他命相比，索里昂在体内作用的差异。这些数据表明，索里昂可能为治疗嗜睡症或 OSA 患者的 ES 提供重要的治疗进展。
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