Metabotropic Glutamate Receptors in the Basal Ganglia

基底神经节的代谢型谷氨酸受体

基本信息

批准号：
8444415
负责人：
COLLEEN M NISWENDER
金额：
$ 22.58万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8444415
关键词：
Acute Adverse effects Affinity Agonist Animals Antiparkinson Agents Basal Ganglia Behavioral Binding Binding Sites Brain Cessation of life Chemical Structure Chemosensitization Clinical Data Development Disease Progression Disease model Dopamine Dopamine Agonists Drug Kinetics Drug Targeting Exhibits GRM5 gene Glutamate Receptor Glutamates Gold Hour In Vitro Knowledge Lateral Lead Lesion Ligands Location Mediating Metabotropic Glutamate Receptors Modeling Molecular Molecular Bank Motor Olfactory tract Oxidopamine Parkinson Disease Parkinsonian Disorders Patients Pharmaceutical Preparations Phenotype Play Pre-Clinical Model Property Publishing Replacement Therapy Reporting Rodent Rodent Model Role Site Slice Substantia nigra structure Synapses Synaptic Transmission Testing Therapeutic Tissues Translating base dopaminergic neuron drug candidate drug development high throughput screening in vitro activity in vivo metabotropic glutamate receptor 4 metabotropic glutamate receptor 8 motor deficit motor impairment novel novel therapeutics pars compacta piriform cortex pre-clinical preference receptor receptor function research study response standard care tissue preparation tool

项目摘要

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.

描述（由申请人提供）：帕金森氏病（PD）是由于多巴胺能神经元在基底神经节（BG）的大量Nigra Pars Compacta（SNC）中死亡的结果。替代丢失的多巴胺是标准PD处理，是通过管理多巴胺前体L-DOPA或多巴胺受体激动剂来实现的。但是，多巴胺替代疗法会导致严重的副作用，并最终在许多患者中失去疗效。对BG内神经通路的了解增加导致发展了新的治疗策略，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BG突触的突触传播，并具有作为PD处理的新靶标。最近，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研究的详细分子分析进行了令人兴奋的翻译进展。现在，我们已经生成了初步数据，表明MGLU8还可以调节BG运动回路中的活性，并具有潜在的效用，作为非多巴胺能PD处理的新靶标。先前的研究表明，在急性PD模型中，MGLU8的激活不会逆转运动障碍。然而，我们在这里的初步研究表明，MGLU8的激活在经历了长期多巴胺耗竭或阻塞的动物中具有强大的反帕金森活性，这表明MGLU8可能代表了一旦PD进展开始就可以操纵的新目标。但是，由于药物候选物的高度选择性活化剂，因此无法获得适合优化的特性，无法进一步推进MGLU8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保守性，很难开发具有高选择性和合适的药代动力学特性的配体，这些配体在正常位点结合。在我们用于其他MGLU的策略的基础上，我们最近开发了MGLU8，VU0155094的阳性变构调节剂（PAM），该调制器对MGLU8对MGLU4而言是高度选择性的。 MGLU4是一种相关的谷氨酸受体，它也介导了基底神经节的作用。 MGLU8对MGLU4的VU0155094的选择性表明，我们现在具有适当的工具化合物，可以开始验证MGLU8在PD的延长多巴胺消耗模型中的作用。我们将检验以下假设：VU0155094将调节已知在脑切片中对MGLU8激动剂响应的突触中的MGLU8测定的突触传播。此外，我们将检验以下假设：MGLU8 PAM（如MGLU8激动剂）在多巴胺消耗的啮齿动物模型中具有抗PD效应。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pharmacological stimulation of metabotropic glutamate receptor type 4 in a rat model of Parkinson's disease and L-DOPA-induced dyskinesia: Comparison between a positive allosteric modulator and an orthosteric agonist.

DOI：
10.1016/j.neuropharm.2015.02.023
发表时间：
2015-08
期刊：
Neuropharmacology
影响因子：
4.7
作者：
Iderberg H;Maslava N;Thompson AD;Bubser M;Niswender CM;Hopkins CR;Lindsley CW;Conn PJ;Jones CK;Cenci MA
通讯作者：
Cenci MA

Progress toward advanced understanding of metabotropic glutamate receptors: structure, signaling and therapeutic indications.