Allosteric modulation of group III metabotropic glutamate receptor 4: A potential approach to Parkinson's disease treatment
Allosteric modulation of group III metabotropic glutamate receptor 4: A potential approach to Parkinson's disease treatment
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DOI：
10.1073/pnas.1835724100
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发表时间：
2003-11-11
影响因子：
11.1
通讯作者：
Conn, PJ
中科院分区：
文献类型：
--
作者：
Marino, MJ;Williams, DL;Conn, PJ
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。目前的治疗集中在多巴胺替代策略，最终在大多数患者中失败，因为失去疗效和严重的不良反应，随着疾病的进展而恶化。最近手术方法的成功表明，绕过多巴胺系统并恢复基底神经节运动回路平衡的药物干预可能提供有效的治疗策略。我们以前确定代谢型谷氨酸受体4（mGluR 4）作为一个潜在的药物靶点，并预测mGluR 4的选择性激活可以提供姑息治疗PD的好处。我们现在报道N-苯基-7-（羟基亚氨基）环丙烯并[B]色烯-la-甲酰胺（PHCCC）是mGluR 4的选择性变构增效剂。该化合物选择性地增强激动剂诱导的mGluR 4在表达该受体的培养细胞中的活性，并且本身不作为激动剂。此外，PHCCC加强L-（+）-2-氨基-4-膦酰基丁酸在抑制纹状体-苍白球突触传递的作用。调节纹状体-苍白球突触已被提出作为PD的潜在治疗靶点，因为它可以恢复基底神经节运动回路的平衡。与此一致，PHCCC产生了利血平诱导的运动不能在大鼠中的显着逆转。密切相关的类似物7-（羟基亚氨基）环丙色烯-1a-甲酰胺乙酯，不增强mGluR 4，在这个模型中没有效果。这些结果是mGluRs的变构增效剂的体内行为效应的证据，并表明mGluR 4的增效作用可能是治疗PD的有用的治疗方法。
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-la-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.