Metabotropic Glutamate Receptor 5 as a Target for the Treatment of Depression and Smoking: Robust Preclinical Data but Inconclusive Clinical Efficacy.
Metabotropic Glutamate Receptor 5 as a Target for the Treatment of Depression and Smoking: Robust Preclinical Data but Inconclusive Clinical Efficacy.
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DOI：
10.1016/j.biopsych.2018.03.001
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发表时间：
2018-06-01
影响因子：
10.6
通讯作者：
Bespalov A
中科院分区：
文献类型：
--
作者：
Barnes SA;Sheffler DJ;Semenova S;Cosford NDP;Bespalov A
新型药理学化合物改善临床前模型结果的能力通常不能转化为临床疗效。精神疾病没有生物学界限，识别机制以改善临床前和临床研究领域之间的转化瓶颈是一项重要且具有挑战性的任务。谷氨酸传递在几种神经精神疾病中被破坏。代谢型谷氨酸（mGlu）受体代表了不同类型的受体，有助于兴奋性神经传递。鉴于广泛的，但区域特异性的表达方式，开发药理学化合物来调节mGlu受体活性提供了一个机会，微妙地和选择性地调节兴奋性神经传递。本文综述了mGlu5受体破坏在重性抑郁障碍（MDD）和物质使用障碍（SUD）中的潜在作用。我们概述了靶向mGlu5受体治疗这些疾病的理由，总结了负调节mGlu5受体作为MDD和尼古丁依赖治疗靶点的临床前证据，并强调了最近临床试验的结果。虽然mGlu5负变构调节的证据在临床前研究中很有希望，但这些有益作用尚未转化为临床疗效。在这篇综述中，我们已经确定了可能导致临床翻译不佳的关键挑战，并提供了建议的方法，以潜在地改善从临床前到临床领域的翻译。这种方法可能会增加临床试验的成功率，并可能减少精神疾病药物发现中存在的翻译瓶颈。
The ability of novel pharmacological compounds to improve outcomes in preclinical models is often not translated into clinical efficacy. Psychiatric disorders do not have biological boundaries and identifying mechanisms to improve the translational bottleneck between preclinical and clinical research domains is an important and challenging task. Glutamate transmission is disrupted in several neuropsychiatric disorders. Metabotropic glutamate (mGlu) receptors represent a diverse class of receptors that contribute to excitatory neurotransmission. Given the wide, yet region-specific manner of expression, developing pharmacological compounds to modulate mGlu receptor activity provides an opportunity to subtly and selectively modulate excitatory neurotransmission. This review focuses on the potential involvement of mGlu5 receptor disruption in major depressive disorders (MDD) and substance use disorders (SUD). We have provided an overview of the justification of targeting mGlu5 receptors in the treatment of these disorders, summarized the preclinical evidence for negatively modulating mGlu5 receptors as a therapeutic target for MDD and nicotine dependence and highlighted the outcomes of recent clinical trials. While the evidence of mGlu5 negative allosteric modulation has been promising in preclinical investigations, these beneficial effects have not translated into clinical efficacy. In this review, we have identified key challenges that may contribute to poor clinical translation and provided suggested approaches moving forward to potentially improve the translation from preclinical to clinical domains. Such approaches may increase the success of clinical trials, and may reduce the translational bottleneck that exists in drug discovery for psychiatric disorders.
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影响因子：
15.9
作者：
Der-Avakian A;Markou A
通讯作者：
Markou A
影响因子：
4.4
作者：
Elmenhorst, David;Mertens, Kristina;Bauer, Andreas
通讯作者：
Bauer, Andreas
DOI：
10.1155/2014/652750
发表时间：
2014
期刊：
ISRN psychiatry
影响因子：
--
作者：
Abou Farha K;Bruggeman R;Baljé-Volkers C
通讯作者：
Baljé-Volkers C
影响因子：
4.8
作者：
Dunlop, Boadie W.;Betancourt, Yara;Mayberg, Helen S.
通讯作者：
Mayberg, Helen S.
DOI：
10.1073/pnas.1210984110
发表时间：
2013-01-08
影响因子：
11.1
作者：
Akkus, Funda;Ametamey, Simon M.;Hasler, Gregor
通讯作者：
Hasler, Gregor