Targeting of alpha7 nAChR for therapeutic effects

靶向 α7 nAChR 以获得治疗效果

基本信息

批准号：
9205232
负责人：
ROGER L PAPKE
金额：
$ 42.46万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-05-01 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9205232
关键词：
A549 Adverse effects Agonist Alzheimer&apos s Disease Amination Amines Apoptotic Arthritis Asthma Binding Binding Sites Biochemical Biological Assay Biological Models Brain Cell Line Cells Central Nervous System Diseases Choline Cognition Cognition Disorders Crystallization Data Dependence Development Disease Docking Down-Regulation Drug Binding Site Effectiveness Electrophysiology (science)Elements Face Formalin GTS-21 Homology Modeling Immune Immune system Induction of Apoptosis Inflammation Inflammatory Inflammatory Response Ion Channel Length Leukocytes Ligand Binding Ligand Binding Domain Ligands Lung Adenocarcinoma Mediating Mediator of activation protein Medicine Modeling Molecular Molecular Chaperones Molecular Conformation Mutation Neuroblastoma Neuroglia Neurons Neurotransmitters Nicotinic Receptors Pain Penetration Peripheral Pharmaceutical Preparations Pharmacology Phase Phenotype Probability Process Production Property Protein Subunits Proteins Regulation Role Schizophrenia Sepsis Signal Transduction Signal Transduction Induction Site Structure T-Lymphocyte Testing Therapeutic Effect Therapeutic Uses Thromboplastin Tissues Transfection Work alpha-bungarotoxin receptor base cell type cytokine desensitization design drug candidate experience gene product improved in vivo in vivo Model inflammatory pain knock-down monocyte mutant novel novel drug class novel therapeutics pharmacophore positive allosteric modulator public health relevance receptor receptor function response therapeutic target vector

项目摘要

DESCRIPTION (provided by applicant): The nicotinic acetylcholine receptor (nAChR) α7 subtype has numerous properties that distinguish it from other nAChRs, including activation by both the neurotransmitter ACh and the ubiquitous tissue factor choline, a feature that may be associated with its important functional expression in both neuronal and non-neuronal cells, including cells of the immune system. Expressed in such diverse tissues, α7 nAChR are also recognized as potentially important therapeutic targets for diverse indications including CNS disorders like Alzheimer's disease and schizophrenia, as well as peripheral disorders, especially inflammatory diseases and pain. Traditionally, study of α7 and other nAChR has focused on ligands that activate or antagonize the receptor's ion channel; however, it has recently been shown that the best drugs for treating the peripheral disorders may be those that preferentially induce the alternative conformational states associated with ion channel desensitization. Consistent with the hypothesis that the selective targeting of α7 receptors for peripheral disorders will require qualitatively different drugs from those for CNS disorders, cells which mediate α7 control of inflammation do not have α7 receptors with activatable ion channels, possibly due to the co-expression of other gene products that limit ion channel function and confer distinct pharmacological profiles for α7 function in those cells. We have used electrophysiological and biochemical approaches to determine how the multiple conformational states of α7 are selectively regulated by ligands and have used allosteric modulators to identify novel molecules we characterize as silent agonists. Our data indicate that silent agonists will be useful to selectively target α7 receptors for peripheral diseases, while alternative α7 - selectie agonists with ion channel efficacy may be better for CNS disorders. Drugs with selectivity for specific indications will be less likely to have crossover side effects when used therapeutically. In this project we will continue to refine and develop these concepts for selective targeting of α receptors with silent agonists by testing hypotheses related to a novel pharmacophore(s) for such drugs and by further identifying elements in the ligand binding domain that differentially regulate the stabilization of specific conformational states, including those which are active for signal transduction in non-neuronal cells. We will test hypotheses related to accessory proteins that may differentially regulate α7 function in different cell types. We will test our new ligands and previously identified reference compounds in cell- based assays for the regulation of cytokine production and mediators of signal transduction that are relevant to inflammatory disease and pain. We will also directly evaluate their efficacy in vivo for reducing pain from inflammation. These studies will allow us to test our core hypothesis that the therapeutic targeting of α7 for specific indications will rely on identifying ligands that discriminate betwee channel-dependent and channel-independent signaling modes.

DESCRIPTION (provided by application): The nicotinic acetylcholine receptor (nAChR) α7 subtype has numerous properties that distinguish it from other nAChRs, including activation by both the neurotransmitter ACh and the ubiquitous tissue factor choline, a feature that may be associated with its important functional expression in both neuronal and non-neuronal cells, including cells of the immune system. α7NACHR在这种多样性时表达，也被认为是潜在的重要治疗靶标，这些靶标可能是CNS疾病，例如阿尔茨海默氏病和精神分裂症，以及外周疾病，尤其是炎症性疾病和疼痛。传统上，对α7和其他NACHR的研究集中在激活或拮抗接收器离子通道的配体上。 however, it has recently been shown that the best drugs for treating the peripheral disorders may be those that Consistent with the hypothesis that the selective targeting of α7 receptors for peripheral disorders will require qualitatively different drugs from those for CNS disorders, cells which mediate α7 control of inflammation do not have α7 receptors with activatable ion channels, possible due to the co-expression of other gene products that limit ion这些细胞中α7功能的通道功能和会议不同的药理学特征。我们已经使用电生理和生化方法来确定如何通过配体选择性调节多个α7的多构象状态，并使用变构调节剂来识别我们将其表征为无声激动剂的新型分子。我们的数据表明，沉默的激动剂对于选择性地靶向α7受体而言是有用的，而替代性α7-具有离子通道有效性的替代α7 -selectie激动剂对中枢神经系统疾病可能更好。当热使用时，具有选择性的特定适应症的药物对交叉副作用的可能性较小。在这个项目中，我们将通过测试与新型药物团相关的假设，通过对这种药物的新型假设进行测试，并通过进一步识别配体结合结构域中的元素，该假设与稳定性不同的稳定蛋白可以调节辅助蛋白相关的细胞类型不同，从而使这些概念差异化。我们将测试我们的新配体并以前在基于细胞的测定中发现了与炎症性疾病和疼痛相关的信号转导介质调节的基于细胞的参考化合物。我们还将直接评估它们在体内减轻炎症疼痛的效率。这些研究将使我们能够检验我们的核心假设，即针对特定指示的α7的治疗靶向将依赖于识别歧视彼此依赖于通道依赖性和与通道无关的信号传导模式的配体。