Highly Selective Muscarinic Agents as Antiparkinsonian Therapy

高选择性毒蕈碱剂作为抗帕金森病治疗

基本信息

批准号：
8011786
负责人：
P Jeffrey Conn
金额：
$ 25.97万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8011786
关键词：
Acute Address Adverse effects Animal Model Animals Antiparkinson Agents Area Basal Ganglia Behavioral Cell Nucleus Cells Chronic Clinical Corpus striatum structure Data Development Disease Dopamine Electrophysiology (science)Immunohistochemistry Impairment In Vitro Individual Injection of therapeutic agent Knockout Mice Lead Ligands Motor Muscarinic Acetylcholine Receptor Muscarinic M1 Receptor Muscarinics N-Methyl-D-Aspartate Receptors Neurons Neurotransmitters Output Parkinson Disease Parkinsonian Disorders Patients Pedunculopontine Tegmental Nucleus Peripheral Pharmaceutical Preparations Physiological Regulation Relative (related person)Replacement Therapy Rodent Model Role Series Staging Structure of subthalamic nucleus Substantia nigra structure Symptoms Synapses Synaptic Transmission System Testing Thalamic structure Treatment Efficacy base cholinergic dopaminergic neuron effective therapy improved in vivo neuronal excitability neuronal patterning novel novel therapeutic intervention pars compacta patch clamp receptor research study response traditional therapy transmission process

项目摘要

Antagonists at muscarinic acetylcholine receptors (mAChRs) are commonly used in parkinsonian patients as an alternative to dopaminergic replacement therapies. The mAChR antagonists are very effective for treating symptoms, but their clinical utility is often limited by significant central and peripheral side effects. It is likely that the adverse effects of mAChR antagonists are due to the fact that available compounds are nonselective and have similar antagonist potencies at all of the five mAChR subtypes (termed Ml - M5). Development of an understanding of the individual mAChR subtypes involved in modulating basal ganglia function could provide a basis for development of mAChR antagonists that selectively block individual mAChR subtypes and may have antiparkinsonian efficacy with reduced adverse effect liability compared with the non-selective mAChR antagonists. We have made a major breakthrough in developing the first highly selective allosteric modulators of M1, M4, and M5 mAChR subtypes. In preliminary studies, we found that Ml, M4 and M5 mAChRs regulate neuronal excitability and inhibitory synaptic transmission in key nuclei of the basal ganglia. Specifically, the available data suggest to us that blockade of Ml and/or M4 mAChRs could have antiparkinsonian effects through reduction of pathologically increased and abnormally patterned neuronal activity in the subthalamic nucleus or the substantia nigra pars reticulata, while M5 activation may be beneficial, as M5 receptors appear to depolarize neurons in the substantia nigra pars compacta which may increase striatal dopamine levels. In the proposed studies, we plan to test these hypotheses by a thorough analysis of the electrophysiologic effects of our novel subtype-specific mAChR active compounds, and through in-vivo testing of these agents in acute and chronic rodent models of Parkinson's disease. Parallel immunohistochemcal studies (Core B) will examine the synaptic and subcellular distribution of the mAChR subtypes in the subthalamic nucleus and substantia nigra. These experiments are highly significant, as they may identify new classes of antiparkinsonian agents that promise effective treatment of parkinsonian patients with fewer side effects than currently possible.

毒蕈碱乙酰胆碱受体（MACHR）的拮抗剂通常在帕金森患者中用作多巴胺能替代疗法的替代方法。 MACHR拮抗剂非常有效地治疗症状，但是它们的临床效用通常受到大量中央和外围副作用的限制。 MACHR拮抗剂的不利影响可能是由于可用化合物是非选择性的，并且在五个MACHR亚型（称为ML -M5）中具有相似的拮抗作用。对调节基底神经节功能的各个MACHR亚型的了解可以为开发MACHR拮抗剂的发展提供基础，这些MACHR拮抗剂有选择地阻止单个MACHR亚型，并且可能具有与非选择性MACHR拮抗剂相比的不良反应责任，并可能具有抗parkinsonian的功效。我们在开发M1，M4和M5 MACHR子类型的第一个高度选择性的变构调节剂方面取得了重大突破。在初步研究中，我们发现ML，M4和M5 MACHR调节基底神经节关键核中的神经元兴奋性和抑制性突触传播。具体而言，可用的数据向我们表明，通过减少病理上增加的病理上增加和异常的神经元活性，对ML和/或M4 MACHR的封锁可能具有反帕金森氏症的影响多巴胺水平。在拟议的研究中，我们计划通过对新型亚型特异性MACHR活性化合物的电生理效应进行彻底分析，并通过对这些药物的急性和慢性啮齿动物模型中的这些药物的测试来检验这些假设。平行的免疫组织化学研究（CORE B）将检查丘脑下核和黑质Nigra中MACHR亚型的突触和亚细胞分布。这些实验非常重要，因为它们可能会确定新型的抗帕金森氏菌药物，这些药物有效治疗帕金森氏症患者的副作用少于目前。