Marino Michael J, Williams David L, O'Brien Julie A, Valenti Ornella, McDonald Terrence P, Clements Michelle K, Wang Ruiping, DiLella Anthony G, Hess J Fred, Kinney Gene G, Conn P Jeffrey
Department of Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA.
Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13668-73. doi: 10.1073/pnas.1835724100. Epub 2003 Oct 30.
Parkinson's disease (PD) is a debilitating movement disorder that afflicts >1 million people in North America. Current treatments focused on dopamine-replacement strategies ultimately fail in most patients because of loss of efficacy and severe adverse effects that worsen as the disease progresses. The recent success of surgical approaches suggests that a pharmacological intervention that bypasses the dopamine system and restores balance in the basal ganglia motor circuit may provide an effective treatment strategy. We previously identified the metabotropic glutamate receptor 4 (mGluR4) as a potential drug target and predicted that selective activation of mGluR4 could provide palliative benefit in PD. We now report that N-phenyl-7-(hydroxylimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC) is a selective allosteric potentiator of mGluR4. This compound selectively potentiated agonist-induced mGluR4 activity in cultured cells expressing this receptor and did not itself act as an agonist. Furthermore, PHCCC potentiated the effect of l-(+)-2-amino-4-phosphonobutyric acid in inhibiting transmission at the striatopallidal synapse. Modulation of the striatopallidal synapse has been proposed as a potential therapeutic target for PD, in that it may restore balance in the basal ganglia motor circuit. Consistent with this, PHCCC produced a marked reversal of reserpine-induced akinesia in rats. The closely related analogue 7-(hydroxylimino)cyclopropachromen-1a-carboxamide ethyl ester, which does not potentiate mGluR4, had no effect in this model. These results are evidence for in vivo behavioral effects of an allosteric potentiator of mGluRs and suggest that potentiation of mGluR4 may be a useful therapeutic approach to the treatment of PD.
帕金森病（PD）是一种使人衰弱的运动障碍疾病，在北美影响着超过100万人。目前专注于多巴胺替代策略的治疗方法在大多数患者中最终都会失败，原因是疗效丧失以及随着疾病进展而恶化的严重不良反应。手术方法最近取得的成功表明，一种绕过多巴胺系统并恢复基底神经节运动回路平衡的药物干预可能提供一种有效的治疗策略。我们之前已确定代谢型谷氨酸受体4（mGluR4）为潜在的药物靶点，并预测mGluR4的选择性激活可为帕金森病提供缓解益处。我们现在报告，N-苯基-7-（羟基亚氨基）环丙并[b]色烯-1a-甲酰胺（PHCCC）是mGluR4的选择性变构增强剂。该化合物在表达该受体的培养细胞中选择性增强激动剂诱导的mGluR4活性，且其本身并不充当激动剂。此外，PHCCC增强了L-(+)-2-氨基-4-膦酰丁酸在抑制纹状体苍白球突触传递方面的作用。调节纹状体苍白球突触已被提议作为帕金森病的潜在治疗靶点，因为它可能恢复基底神经节运动回路的平衡。与此一致的是，PHCCC使大鼠中利血平诱导的运动不能得到显著逆转。与之密切相关的类似物7-（羟基亚氨基）环丙并色烯-1a-甲酰胺乙酯，它不能增强mGluR4的活性，在该模型中没有效果。这些结果证明了代谢型谷氨酸受体变构增强剂的体内行为效应，并表明增强mGluR4可能是治疗帕金森病的一种有用的治疗方法。
