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 disorder and substance and/or alcohol use disorders. We provide an overview of the justification of targeting mGlu5 receptors in the treatment of these disorders, summarize the preclinical evidence for negatively modulating mGlu5 receptors as a therapeutic target for major depressive disorders and nicotine dependence, and highlight the outcomes of recent clinical trials. While the evidence of mGlu5 receptor negative allosteric modulation has been promising in preclinical investigations, these beneficial effects have not translated into clinical efficacy. In this review, we identify key challenges that may contribute to poor clinical translation and provide 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.

中文翻译：

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代谢型谷氨酸受体 5 作为治疗抑郁症和吸烟的靶标：可靠的临床前数据，但临床疗效尚无定论


新型药理化合物改善临床前模型结果的能力通常不会转化为临床疗效。精神疾病没有生物学界限，确定改善临床前和临床研究领域之间转化瓶颈的机制是一项重要且具有挑战性的任务。谷氨酸传输在多种神经精神疾病中受到干扰。代谢型谷氨酸 (mGlu) 受体代表了一类有助于兴奋性神经传递的受体。鉴于广泛但区域特异性的表达方式，开发调节 mGlu 受体活性的药理学化合物为微妙且选择性地调节兴奋性神经传递提供了机会。本综述重点关注 mGlu5 受体破坏在重度抑郁症和物质和/或酒精使用障碍中的潜在作用。我们概述了针对 mGlu5 受体治疗这些疾病的合理性，总结了负调节 mGlu5 受体作为重度抑郁症和尼古丁依赖的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 受体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，我们确定了可能导致临床转化不佳的关键挑战，并提供了建议的方法，以可能改善从临床前领域到临床领域的转化。 这些方法可能会提高临床试验的成功率，并可能减少精神疾病药物发现中存在的转化瓶颈。