Kappa-Opioid Antagonists for Psychiatric Disorders: From Bench to Clinical Trials.
Kappa-Opioid Antagonists for Psychiatric Disorders: From Bench to Clinical Trials.
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DOI：
10.1002/da.22500
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发表时间：
2016-10
影响因子：
7.4
通讯作者：
Krystal AD
中科院分区：
文献类型：
--
作者：
Carlezon WA Jr;Krystal AD
kappa -阿片受体（KOR）拮抗剂目前正被考虑用于治疗各种神经精神疾病，包括抑郁、焦虑和药物滥用障碍。减轻压力影响的一般能力，可以触发或加剧这些疾病，可能解释了它们在如此广泛的条件下的功效。它们潜在治疗效果的发现源于临床前研究，该研究旨在描述经验导致伏隔核（NAc）神经适应的分子机制，伏隔核是大脑奖励回路的关键元素。本研究证实，暴露于药物滥用或压力下会增加NAc中转录因子CREB （cAMP反应元件结合蛋白）的活性，从而导致阿片肽dynorphin的表达升高，从而导致抑郁和焦虑相关障碍的核心症状。kors（促啡肽的内源性受体）的破坏会在筛选过程中产生抗抑郁和抗焦虑样的作用，以确定这类标准药物，并减少用于研究成瘾和压力相关障碍的测试中的压力效应。尽管对这一靶点的兴趣很高，但典型的KOR拮抗剂具有非常持久的药效学作用，使临床试验复杂化。短期作用的KOR拮抗剂的发展以及更快的临床试验设计可能很快就会像临床前工作预测的那样，提供这些药物是否有效的见解。如果成功，KOR拮抗剂将在精神病学中代表一个独特的例子，即一类药物的治疗机制在被证明对人类有效之前被理解。
Kappa-opioid receptor (KOR) antagonists are currently being considered for the treatment of a variety of neuropsychiatric conditions, including depressive, anxiety, and substance abuse disorders. A general ability to mitigate the effects of stress, which can trigger or exacerbate these conditions, may explain their putative efficacy across such a broad array of conditions. The discovery of their potentially therapeutic effects evolved from preclinical research designed to characterize the molecular mechanisms by which experience causes neuroadaptations in the nucleus accumbens (NAc), a key element of brain reward circuitry. This research established that exposure to drugs of abuse or stress increases the activity of the transcription factor CREB (cAMP response element binding protein) in the NAc, which leads to elevated expression of the opioid peptide dynorphin, which in turn causes core signs of depressive- and anxiety-related disorders. Disruption of KORs—the endogenous receptors for dynorphin—produces antidepressant- and anxiolytic-like actions in screening procedures that identify standard drugs of these classes, and reduces stress effects in tests used to study addiction and stress-related disorders. Although interest in this target is high, prototypical KOR antagonists have extraordinarily persistent pharmacodynamic effects that complicate clinical trials. The development of shorter-acting KOR antagonists together with more rapid designs for clinical trials may soon provide insight on whether these drugs are efficacious as would be predicted by preclinical work. If successful, KOR antagonists would represent a unique example in psychiatry where the therapeutic mechanism of a drug class is understood before it is shown to be efficacious in humans.