Metabotropic Glutamate Receptors in the Basal Ganglia

描述(申请人提供)：帕金森病(PD)是由基底节(BG)的实质黑质致密部(SNC)中的多巴胺能神经元死亡引起的。替代丢失的多巴胺是标准的帕金森病治疗方法，可通过使用多巴胺前体L-多巴或多巴胺受体激动剂来实现。然而，多巴胺替代疗法会导致严重的副作用，最终对许多患者无效。对BG内神经回路的了解增加导致了新的治疗策略的发展，以纠正BG缺陷和治疗PD患者。代谢性谷氨酸受体(MGlus)调节几个关键的BG突触的突触传递，有可能成为治疗PD的新靶点。最近，通过将新的mGlu配体的发现和详细的分子分析与电生理和行为研究相结合，mGlus 4和5在翻译上取得了令人兴奋的进展。我们现在已经产生了初步的数据，表明mGlu8也可能调节BG马达回路的活动，并具有作为非多巴胺能PD治疗的新靶点的潜在用途。先前的研究表明，激活mGlu8并不能逆转急性帕金森病模型的运动障碍。然而，我们的初步研究表明，在经历了长时间的多巴胺耗竭或阻断的动物中，mGlu8的激活具有强大的抗帕金森病活性，这表明mGlu8可能是一个新的靶点，一旦帕金森病进展开始，就可以对其进行操纵。然而，具有适合作为候选药物进行优化的高选择性mGlu8激活剂一直无法进一步推进mGlu8激活可能对帕金森病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结合在邻位上。在我们用于其他mGlu的策略的基础上，我们最近开发了一种mGlu8的正变构调节剂(PAM)，VU0155094，它对mGlu8和mGlu4具有高度的选择性。MGlu4是一种相关的谷氨酸受体，也在基底节介导作用；VU0155094对mGlu8的选择性高于mGlu4，这表明我们现在有了一种适当的工具化合物来开始验证mGlu8在帕金森病延长的多巴胺耗竭模型中的作用。我们将测试这一假设，即VU0155094将在已知对脑片中mGlu8激动剂有反应的突触上调节mGlu8冥想的突触传递。此外，我们将测试假设，即mGlu8 PAM，与mGlu8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。 公共卫生相关性：我们有初步数据显示，代谢性谷氨酸受体8(MGlus)激动剂在长期(但不是急性)多巴胺耗竭后显示出抗帕金森症的活性。我们将测试一种新发现的mGlu8正变构调节剂将增强特定脑突触的已知mGlu8介导的反应的假设。然后，我们将评估这种mGlu8 PAM在帕金森氏病的几种啮齿动物模型中显示出抗帕金森病活性的能力。

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. PUBLIC HEALTH RELEVANCE: We have preliminary data showing that an agonist of metabotropic glutamate receptor 8 (mGlus) exhibits antiparkinsonian activity after prolonged, but not acute, dopamine depletion. We will test the hypothesis that a newly discovered positive allosteric modulator of mGlu8 will potentiate known mGlu8-mediated responses at specific brain synapses. We will then assess the ability of this mGlu8 PAM to exhibit antiparkinsonian activity in several rodent models of Parkinson's disease.