Department of Pharmacology, Vanderbilt Program in Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232-36000, USA.
Future Med Chem. 2009 Jun;1(3):501-13. doi: 10.4155/fmc.09.38.
Although Parkinson's disease was first diagnosed nearly 200 years ago, its effective treatment still remains elusive for most of those diagnosed. The gold standard of treatment for most patients is 3,4-dihydroxy-L-phenylalanine. This drug works for most individuals early in the disease; however, resistant symptoms start to emerge after several years of treatment. There has been increased interest in finding novel therapies to help Parkinson's disease patients. Such strategies may have the benefit of not only treating the symptomatic issues of the disorder, but might also offer promise in protecting dopaminergic neurons from further degeneration. One such target that is now receiving much attention from the scientific community is the metabotropic glutamate receptor mGluR4. In this article, we briefly review Parkinson's disease and then recent work in the mGluR area, with a focus on the efforts being made toward finding and optimizing novel mGluR4 positive allosteric modulators (PAMs). Preclinically in rodent models, mGluR4 activation has offered much promise as a novel treatment of Parkinson's disease. Additionally, the specific use of PAMs, rather than direct-acting agonists at the orthosteric glutamate site, continues to be validated as a viable treatment option for this target. It is anticipated that continued progress in this area will further our understanding of the potential of mGluR4 modulation as a novel symptomatic and potentially disease-modifying treatment for Parkinson's disease.
虽然帕金森病在近 200 年前首次被诊断出来，但对于大多数被诊断出的患者来说，其有效的治疗方法仍然难以捉摸。大多数患者的治疗金标准是 3,4-二羟基-L-苯丙氨酸。这种药物在疾病早期对大多数人有效；然而，在治疗几年后，耐药症状开始出现。人们越来越关注寻找新的治疗方法来帮助帕金森病患者。这些策略不仅可能治疗该疾病的症状问题，而且还可能有望保护多巴胺能神经元免受进一步退化。目前，科学界非常关注的一个目标是代谢型谷氨酸受体 mGluR4。在本文中，我们简要回顾了帕金森病，然后介绍了 mGluR 领域的最新工作，重点介绍了寻找和优化新型 mGluR4 正变构调节剂 (PAM) 的努力。在啮齿动物模型中进行的临床前研究表明，mGluR4 的激活作为帕金森病的一种新的治疗方法具有很大的前景。此外，使用 PAMs 而不是直接作用于正位谷氨酸位点的激动剂，继续被验证为该靶点的可行治疗选择。预计在这一领域的持续进展将进一步加深我们对 mGluR4 调节作为帕金森病新型症状和潜在疾病修饰治疗的潜力的理解。
