Novel, subtype selective potentiators of nicotinic acetycholine receptors

烟碱乙酰胆碱受体的新型亚型选择性增强剂

• 批准号: 7699276
• 负责人: Marvin Kenneth Schulte
• 金额: $ 33.52万
• 依托单位: UNIVERSITY OF ALASKA FAIRBANKS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7699276
• 关键词: Acetylcholine; Acetylcholinesterase Inhibitors; Adverse effects; Alzheimer' s Disease; Attention Deficit Disorder; Autistic Disorder; Awareness; Benzodiazepines; Binding; Binding Sites; Biological Factors; Central Nervous System Diseases; Data; Disease; Evaluation; Family; Frontal Lobe Epilepsy; GABA Receptor; Galantamine; Gilles de la Tourette syndrome; Goals; Government; Gray unit of radiation dose; Hand; Kinetics; Laboratories; Lead; Left; Ligands; Maps; Molecular Models; Mutagenesis; Mutation; Neurons; Nicotinic Receptors; North Sea; Parkinson Disease; Patients; Persons; Pharmaceutical Preparations; Physostigmine; Positioning Attribute; Process; Property; Research; Role; Schizophrenia; Sea; Series; Site; Site-Directed Mutagenesis; Therapeutic; analog; improved; inhibitor/antagonist; interest; molecular modeling; nervous system disorder; novel; novel strategies; pharmacophore; public health relevance; receptor; receptor binding; reconstruction; response

DESCRIPTION (provided by applicant): Nicotinic receptors have been implicated in a broad range of neurological disorders including Alzheimer's disease (AD), Schizophrenia, Autism, Frontal Lobe Epilepsy, Parkinson's disease, Tourette Syndrome and Attention Deficit Disorder. Given the increasing awareness of the role of nicotinic receptors in neurological disorders, it is not surprising that there is intense interest in developing therapeutics aimed at altering the expression or function of this important receptor family. A novel strategy for targeting nAChR subtypes is the identification of "unconventional" or allosteric modulators. Highly selective modulators would be extremely valuable in investigating disease processes and as potential therapeutic drugs. Unfortunately, currently available potentiating agents typically display broad selectivity (although there have been some recent advances in 7 selective potentiators). The recent discovery of a natural product obtained from the Bryozoan, Flustra foliacea provides an exciting opportunity to develop a new class of selective modulatory agents. This compound (d-formylflustrabromide - dFBr) is a highly selective positive allosteric modulator of a4b2 nAChRs. Along with our collaborators, we have synthesized dFBr and evaluated its action on a4b2 receptors. This compound displays a number of properties that make it an ideal lead molecule. Our data suggest that dFBr would provide selective amplification of ACh responses with little change in response kinetics. The primary aims of this proposal are to: 1) Characterize the interaction of the dFBr class of compounds with the a4b2 receptor and 2) Synthesize and characterize new, optimized dFBr type ligands. These independent but mutually synergistic aims are focused on developing a fundamental understanding of dFBr action and interaction with this important receptor. We have already made significant progress in both aims. Preliminary mutagenesis data indicates a putative binding site at a subunit interface equivalent to the benzodiazepine binding site of GABA receptors and we have identified an improved dFBr analog in our preliminary synthetic studies that retains the ability to potentiate a4b2 receptors but without the inhibitory component at high concentrations that is a problem with dFBr itself. The current proposal expands our studies to characterization of dFBr's actions on the a4b2 receptor, mapping the binding domain and developing a refined dFBr pharmacophore. PUBLIC HEALTH RELEVANCE: This project explores the potential of a recently discovered natural product "d- formylflustrabomide" (obtained originally from a species of Bryozoan or "Sea Mat" found in the North Sea) as a lead molecule for a new class of drugs aimed at the treatment of CNS disorders such as Alzheimer's disease, Autism and Schizophrenia. The goal of this study is to develop the natural product into a more usable form with increased potency and less potential side effects. Since this is a new type of drug, it may open up new avenues for understanding and treating these diseases.

描述（由申请人提供）：烟碱受体已与包括阿尔茨海默氏病（AD），精神分裂症，自闭症，额叶癫痫，帕金森氏病，图雷内特综合症和注意力缺陷障碍在内的广泛神经系统疾病有关。鉴于人们对烟碱受体在神经系统疾病中的作用的认识越来越多，毫不奇怪，人们对开发旨在改变这种重要受体家族的表达或功能的治疗剂具有强烈的兴趣。靶向NACHR亚型的新型策略是鉴定“非常规”或变构调节剂。高度选择性调节剂在研究疾病过程和作为潜在治疗药物方面将非常有价值。不幸的是，当前可用的增强剂通常显示出广泛的选择性（尽管有7位选择性增强器的最新进展）。最近发现从Bryozoan获得的天然产品，Flustra Foriacea为开发新的选择性调节剂提供了一个令人兴奋的机会。该化合物（D -Formylflustrabromide -dfbr）是A4B2 NACHR的高度选择性阳性变构调节剂。与我们的合作者一起，我们合成了DFBR，并评估了其对A4B2受体的作用。该化合物显示出许多使其成为理想铅分子的特性。我们的数据表明，DFBR将提供ACH响应的选择性放大，而反应动力学的变化很小。该建议的主要目的是：1）表征化合物与A4B2受体的相互作用，以及2）合成并表征新的，优化的DFBR型配体。这些独立但相互协同的目的集中在对DFBR作用和与该重要受体相互作用的基本理解中发展。我们已经在这两个目标上都取得了重大进展。初步诱变数据表明，与GABA受体的苯二氮卓类结合位点等效的亚基界面处的假定结合位点，我们在初步合成研究中确定了改善的DFBR类似物，该研究保留了能够增强A4B2受体的能力，但没有抑制性成分，但在高度浓度中没有抑制性成分，而该浓度是DFBR的高度问题。当前的建议将我们的研究扩展到了DFBR对A4B2受体的作用的表征，映射结合域并开发了精制的DFBR药理。公共卫生相关性：该项目探讨了最近发现的天然产品“ D- emylflustrabomide”（最初是从北海发现的Bryozoan或“ Sea Mat”的物种获得的）作为一种新药物的铅分子，旨在治疗CNS疾病，例如治疗CNS疾病，例如阿尔茨海默氏病的疾病，Autismism和Schizophrenia和Schizophrenia。这项研究的目的是将天然产物发展为更可用的形式，并增加效力和潜在的副作用。由于这是一种新型药物，因此它可能为理解和治疗这些疾病开辟了新的途径。