Metabotropic Glutamate Receptors in the Basal Ganglia

描述（由申请人提供）：帕金森病（PD）是由基底神经节（BG）的黑质部（SNc）中多巴胺能神经元死亡引起的。丢失的多巴胺的替代是标准的PD治疗，并且通过施用多巴胺前体L-DOPA或多巴胺受体激动剂来实现。然而，多巴胺替代疗法会引起严重的副作用，并最终在许多患者中失去疗效。对BG内神经回路的了解增加，导致开发了新的治疗策略来纠正BG缺陷和治疗PD患者。代谢型谷氨酸受体（mGlus）调节几个关键BG突触的突触传递，并有可能成为PD治疗的新靶点。通过将新型mGlu配体的发现和详细的分子分析与电生理学和行为学研究相结合，mGlus 4和5最近取得了令人兴奋的翻译进展。我们现在已经产生了初步的数据表明，mGlu 8也可以调节BG运动回路的活动，并有潜在的效用，作为一个新的目标，非多巴胺能PD治疗。先前的研究表明，激活mGlu 8不会逆转急性PD模型中的运动障碍。然而，我们的初步研究表明，mGlu 8的激活在经历了长时间多巴胺耗竭或阻断的动物中具有强大的抗帕金森病活性，这表明mGlu 8可能代表了一个新的靶点，一旦PD进展开始，就可以操纵它。然而，具有适合作为候选药物优化的特性的mGlu 8的高选择性激活剂已经无法进一步推进mGlu 8激活可能在PD中具有治疗益处的假设。 基于谷氨酸结合位点的高度保守性，很难开发出具有高选择性和合适的药代动力学性质的配体，其结合在正构位点。基于我们用于其他mGlus的策略，我们最近开发了mGlu 8的正变构调节剂（PAM），VU 0155094，其对mGlu 8相对于mGlu 4具有高度选择性。mGlu 4是一种相关的谷氨酸受体，也介导基底神经节中的作用; VU 0155094对mGlu 8的选择性超过mGlu 4，表明我们现在有了适当的工具化合物来开始验证mGlu 8在PD的长期多巴胺耗竭模型中的作用。我们将测试的假设，即VU 0155094将调制mGlu 8介导的突触传递在突触已知响应于mGlu 8激动剂在脑切片。此外，我们将检验mGlu 8 PAM与mGlu 8激动剂一样在长期多巴胺耗竭的啮齿动物模型中具有抗PD作用的假设。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) results from the death of dopaminergic neurons in the substantial nigra pars compacta (SNc) of the basal ganglia (BG). Replacement of lost dopamine is the standard PD treatment and is achieved by administering the dopamine precursor L-DOPA or dopamine receptor agonists. Dopamine replacement therapies, however, cause severe side effects and eventually lose efficacy in many patients. Increased understanding of neurocircuitry within the BG has led to the development of new therapeutic strategies to correct BG deficits and treat PD patients. The metabotropic glutamate receptors (mGlus) regulate synaptic transmission at several critical BG synapses and have potential as novel targets for PD treatment. Exciting translational advances have recently been made for mGlus 4 and 5 by integrating discovery and detailed molecular analyses of novel mGlu ligands with electrophysiological and behavioral studies. We have now generated preliminary data suggesting that mGlu8 may also regulate activity in the BG motor circuit and have potential utility as a novel target for non-dopaminergic PD treatments. Previous studies have suggested that activation of mGlu8 does not reverse motor impairments in acute PD models. However, our preliminary studies here show that activation of mGlu8 has robust antiparkinsonian activity in animals that have undergone prolonged dopamine depletion or blockade, suggesting that mGlu8 may represent a new target that could be manipulated once PD progression begins. However, highly selective activators of mGlu8 with properties suitable for optimization as drug candidates have been unavailable to further advance the hypothesis that mGlu8 activation may have therapeutic benefit in PD. Based on the high conservation of the glutamate binding site, it has been difficult to develop ligands with high selectivity and suitable pharmacokinetic properties that bind at the orthosteric site. Building upon a strategy we have used for other mGlus, we have recently developed a positive allosteric modulator (PAM) of mGlu8, VU0155094, which is highly selective for mGlu8 versus mGlu4. mGlu4 is a related glutamate receptor that also mediates effects in the basal ganglia; selectivity of VU0155094 for mGlu8 over mGlu4 indicates that we now have an appropriate tool compound to begin validating a role of mGlu8 in prolonged dopamine depletion models of PD. We will test the hypothesis that VU0155094 will modulate mGlu8-meditated synaptic transmission at synapses known to respond to mGlu8 agonists in brain slices. Additionally, we will test the hypothesis that mGlu8 PAMs, like mGlu8 agonists, have anti-PD effects in rodent models of prolonged dopamine depletion.