VMAT2抑制剂和Ingrezza (Valbenazine)通路。

Q1 Pharmacology, Toxicology and Pharmaceutics
Progress in medicinal chemistry Pub Date : 2018-01-01 Epub Date: 2018-03-07 DOI:10.1016/bs.pmch.2017.12.002
Nicole D Harriott, John P Williams, Evan B Smith, Haig P Bozigian, Dimitri E Grigoriadis
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引用次数: 15

摘要

多巴胺能系统在中枢神经系统中起着关键作用,调节执行功能、觉醒、奖励和运动控制。这种关键单胺能系统的失调与中枢神经系统疾病有关,包括精神分裂症、帕金森病和注意缺陷多动障碍和成瘾等疾病。通过调节多巴胺活性来改变多巴胺能系统的药物已经成功地证明了治疗这些疾病的临床疗效。具体来说,抗精神病药物,无论是典型的还是非典型的,虽然作用于大脑中的许多单胺能系统,但主要是通过抑制突触后多巴胺受体来靶向多巴胺系统。囊泡单胺转运蛋白2 (VMAT2)是一种完整的突触前蛋白,它调节多巴胺和其他单胺从神经元囊泡到突触的包装和随后释放。尽管作用于突触的相反两侧,抗精神病药物和VMAT2抑制剂都能降低中枢多巴胺能系统的活性。迟发性运动障碍是一种以不自主重复运动为特征的疾病,被认为是使用抗精神病药物引起的高多巴胺能状态的结果。Valbenazine (NBI-98854)是一种通过活性代谢物选择性抑制VMAT2的新型化合物,已被开发用于治疗迟发性运动障碍,是首个被批准用于治疗这种疾病的药物。本章描述了valbenazine的发现过程,它的药理学特征,以及它的疗效的临床前和临床证据。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
VMAT2 Inhibitors and the Path to Ingrezza (Valbenazine).

The dopaminergic system plays a key role in the central nervous system, regulating executive function, arousal, reward, and motor control. Dysregulation of this critical monoaminergic system has been associated with diseases of the central nervous system including schizophrenia, Parkinson's disease, and disorders such as attention deficit hyperactivity disorders and addiction. Drugs that modify the dopaminergic system by modulating the activity of dopamine have been successful in demonstrating clinical efficacy by providing treatments for these diseases. Specifically, antipsychotics, both typical and atypical, while acting on a number of monoaminergic systems in the brain, primarily target the dopamine system via inhibition of postsynaptic dopamine receptors. The vesicular monoamine transporter 2 (VMAT2) is an integral presynaptic protein that regulates the packaging and subsequent release of dopamine and other monoamines from neuronal vesicles into the synapse. Despite acting on opposing sides of the synapse, both antipsychotics and VMAT2 inhibitors act to decrease the activity of central dopaminergic systems. Tardive dyskinesia is a disorder characterized by involuntary repetitive movements and thought to be a result of a hyperdopaminergic state precipitated by the use of antipsychotics. Valbenazine (NBI-98854), a novel compound that selectively inhibits VMAT2 through an active metabolite, has been developed for the treatment of tardive dyskinesia and is the first drug approved for the treatment of this disorder. This chapter describes the process leading to the discovery of valbenazine, its pharmacological characteristics, along with preclinical and clinical evidence of its efficacy.

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来源期刊
Progress in medicinal chemistry
Progress in medicinal chemistry Pharmacology, Toxicology and Pharmaceutics-Pharmacology
CiteScore
15.60
自引率
0.00%
发文量
6
期刊介绍: This series has a long established reputation for excellent coverage of almost every facet of Medicinal Chemistry and is one of the most respected and instructive sources of information on the subject. The latest volume certifies to the continuing success of a unique series reflecting current progress in a broadly developing field of science.
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