CHOLINESTERASE INHIBITORS THAT ACTIVATE ACETYLCHOLINE RECEPTOR

激活乙酰胆碱受体的胆碱酯酶抑制剂

• 批准号: 6237948
• 负责人: MICHAEL A RAFTERY
• 金额: $ 8.62万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-03-10 至 1998-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6237948
• 关键词: Torpedo; acetylcholine; alternatives to animals in research; analog; carbachol; carbamates; chemical binding; choline; cholinesterase inhibitors; cholinesterases; conformation; fluorescence spectrometry; membrane channels; molecular site; neostigmine; neuromuscular transmission; nicotinic receptors; nuclear magnetic resonance spectroscopy; pharmacology; physostigmine; protein structure function; pyridostigmine; receptor binding; receptor sensitivity

The objective of the proposed research is to delineate the modes of interaction of a particular class of drugs with the nicotinic cholinergic receptor and to elucidate the mechanism by which these drugs activate the ion channel of the receptor to cause cation transport. The drugs to be used are physostigmine, neostigmine and pyridostigmine, which are routinely utilized in the treatment of the human disease Myasthenia Gravis, because of their well known ability to inhibit cholinesterase. These drugs have also been found to be acetylcholine receptor activators that are not inhibited by classical cholinergic antagonists. Because of the chronic nature of Myasthenia Gravis, myasthenic patients are treated with these drugs for many years: their unexpected ability to activate the acetylcholine receptor, and the unusual pharmacological properties of their activating action, may explain the frequent hypersensitivity to these drugs which develop in myasthenic patients. Elucidation of the molecular mechanisms of the dual action of these drugs on the esterase and the acetylcholine receptor, two essential components of neuromuscular transmission, is therefore important for their proper clinical use. At the molecular level, it is of considerable importance to determine whether a neurotransmitter receptor can be activated by a pathway(s) different by that triggered by the native transmitter. The drug action will be studied at the biophysical and biochemical level using spectroscopic approaches, such as fluorescence and nuclear magnetic resonance spectroscopy, and also by chemical labelling approaches, in order to delineate binding and activation mechanisms and to determine the structural domains of the acetylcholine receptor involved in interaction with these drugs.

拟议研究的目的是描述 特定类药物与烟碱胆碱能的相互作用 受体并阐明这些药物激活的机制 受体的离子通道引起阳离子传输。 药物是 使用的是Physostigmine，Neostigmine和Pyridostigmine， 通常用于治疗人类疾病肌无力的治疗 GRAVIS，由于其众所周知的抑制胆碱酯酶的能力。 还发现这些药物是乙酰胆碱受体激活剂 不受经典胆碱能拮抗剂的抑制。 由于 肌无力的疗法，肌无力患者接受治疗 这些药物多年：它们激活的意外能力 乙酰胆碱受体和不寻常的药理特性 它们的激活作用可能解释了频繁的超敏反应 这些药物在肌关系患者中发育。 阐明这些药物双重作用的分子机制 在酯酶和乙酰胆碱受体上，两个必需成分 因此，神经肌肉传播的适当性很重要 临床用途。 在分子水平上，它非常重要 确定是否可以通过A激活神经递质受体 途径是由天然发射机触发的那样不同的。 该药物的作用将在生物物理和生化水平上进行研究 使用光谱法，例如荧光和核磁 共振光谱，也通过化学标记方法 为了描绘结合和激活机制并确定 与相互作用的乙酰胆碱受体的结构结构域 使用这些药物。