Witkin Jeffrey M, Marek Gerard J, Johnson Bryan G, Schoepp Darryle D
Neuroscience Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
CNS Neurol Disord Drug Targets. 2007 Apr;6(2):87-100. doi: 10.2174/187152707780363302.
Current treatments for depression are less than optimal in terms of onset of action, response and remission rates, and side-effect profiles. Glutamate is the major excitatory neurotransmitter controlling synaptic excitability and plasticity in most brain circuits, including limbic pathways involved in depression. Thus, drugs that target glutamate neuronal transmission offer novel approaches to treat depression. Recently, the NMDA receptor antagonist ketamine has demonstrated clinical efficacy in a randomized clinical trial of depressed patients. Metabotropic glutamate (mGlu) receptors function to regulate glutamate neuronal transmission by altering the release of neurotransmitter or modulating the post-synaptic responses to glutamate. Accumulating evidence from biochemical and behavioral studies support the idea that the regulation of glutamatergic neurotransmission via mGlu receptors is linked to mood disorders and that these receptors may serve as novel targets for the discovery of small molecule modulators with unique antidepressant properties. For example, mGlu receptor modulation can facilitate neuronal stem cell proliferation (neurogenesis) and the release of neurotransmitters that are associated with treatment response to depression in humans (serotonin, norepinephrine, dopamine). In particular, compounds that antagonize mGlu2, mGlu3 and/or mGlu5 receptors (e.g. LY341495, MSG0039, MPEP) have been linked to the above pharmacology and have also shown in vivo activity in animal models predictive of antidepressant efficacy such as the forced-swim test. The in vivo actions of these agents can be antagonized by compounds that block AMPA receptors, suggesting that their actions are direct downstream consequences of the enhancement of glutamate neuronal transmission in brain regions involved in depression. These data provide new approaches to finding mechanistically distinct drugs for depression that may have advantages over current therapies for some patients. Moreover, since the mood disorders encompase a non-homogenous set of symptoms, comorbid disorders, and potential etiologies, the rich arsensel that exists within the mGlu receptor families provides an opportunity for both broad and customized therapeutics.
就起效时间、缓解率和副作用等方面而言，目前用于治疗抑郁症的方法并不理想。谷氨酸是控制大多数脑回路（包括与抑郁症相关的边缘通路）突触兴奋性和可塑性的主要兴奋性神经递质。因此，针对谷氨酸神经元传递的药物为治疗抑郁症提供了新的方法。最近，NMDA受体拮抗剂氯胺酮在抑郁症患者的随机临床试验中已显示出临床疗效。代谢型谷氨酸（mGlu）受体通过改变神经递质的释放或调节突触后对谷氨酸的反应来调节谷氨酸神经元传递。生化和行为学研究积累的证据支持这样一种观点，即通过mGlu受体调节谷氨酸能神经传递与情绪障碍有关，并且这些受体可能成为发现具有独特抗抑郁特性的小分子调节剂的新靶点。例如，mGlu受体调节可促进神经元干细胞增殖（神经发生）以及释放与人类抑郁症治疗反应相关的神经递质（血清素、去甲肾上腺素、多巴胺）。特别是，拮抗mGlu2、mGlu3和/或mGlu5受体的化合物（如LY341495、MSG0039、MPEP）已与上述药理学相关联，并且在预测抗抑郁疗效的动物模型（如强迫游泳试验）中也显示出体内活性。这些药物的体内作用可被阻断AMPA受体的化合物拮抗，这表明它们的作用是抑郁症相关脑区谷氨酸神经元传递增强的直接下游后果。这些数据为寻找机制上不同的抗抑郁药物提供了新方法，这些药物对某些患者可能比现有疗法更具优势。此外，由于情绪障碍包括一组异质性的症状、共病和潜在病因，mGlu受体家族中存在的丰富多样性为广泛和定制化治疗提供了机会。
