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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Allosteric modulation of group III metabotropic glutamate receptor 4: A potential approach to Parkinson's disease treatment
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Allosteric modulation of group III metabotropic glutamate receptor 4: A potential approach to Parkinson's disease treatment

机译：第III组代谢型谷氨酸受体4的变构调节：帕金森氏病治疗的潜在方法

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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 potenti-ator 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.
机译：帕金森氏病（PD）是一种使人衰弱的运动障碍，在北美折磨着超过100万人。目前针对多巴胺替代策略的治疗在大多数患者中最终失败，原因是疗效下降以及严重的不良反应随着疾病的进展而恶化。外科手术方法的最新成功表明，绕过多巴胺系统并恢复基底神经节运动回路平衡的药理干预措施可能会提供有效的治疗策略。我们先前确定了代谢型谷氨酸受体4（mGluR4）作为潜在的药物靶标，并预测mGluR4的选择性激活可以在PD中提供姑息性获益。现在，我们报告N-苯基-7-（羟基limino）环丙烷[b] -chromen-1a-羧酰胺（PHCCC）是mGluR4的选择性变构增效剂。该化合物在表达该受体的培养细胞中选择性地增强了激动剂诱导的mGluR4的活性，它本身并不充当激动剂。此外，PHCCC增强了L-（+）-2-氨基-4-膦酰基丁酸在抑制纹状体顶突突触中的传递的作用。已经提出调节纹状体顶突突突作为PD的潜在治疗靶标，因为它可以恢复基底神经节运动回路中的平衡。与此相一致，PHCCC在大鼠中产生了利血平诱导的运动障碍的明显逆转。密切相关的类似物7-（羟基limino）环丙色素n-1a-羧酰胺乙酯，不增强mGluR4的作用，在该模型中无效。这些结果证明了mGluRs的变构增强剂在体内的行为作用，并表明增强mGluR4可能是治疗PD的有用治疗方法。

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