Development of Drugs Acting at Ion Channels

作用于离子通道的药物的开发

• 批准号: 7967317
• 负责人: Kenneth Alan Jacobson
• 金额: $ 12.62万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 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/7967317
• 关键词: Action Potentials; Affect; Agonist; Amyloid Proteins; Apical; Binding Sites; Biological; Biological Process; Brain; Calcium Channel; Calcium ion; Calsequestrin; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular system; Cations; Cavia; Cell membrane; Cells; Chronic; Collaborations; Connecticut; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Epithelial Cells; Failure; Gated Ion Channel; Goals; Heart Hypertrophy; Heart failure; Hereditary Disease; Inflammatory; Interleukin-8; Ion Channel; Lead; Life; Ligands; Longevity; Lung; Mediating; Membrane Potentials; Microglia; Modeling; Molecular Structure; Mus; Muscle Cells; Mutation; Neuraxis; Neurons; Nucleotidases; Nucleotides; P2X-receptor; Pain management; Phenotype; Population; Potassium; Preparation; Process; Proteins; Rattus; Receptor Activation; Regulation; Regulator Genes; Resistance; Rest; Role; Salts; Side; Structure-Activity Relationship; System; Tyrosine; Vasodilator Agents; Ventricular; analog; base; design; dimer; drug development; extracellular; member; mutant; novel; novel strategies; nucleotidase; overexpression; receptor

Cystic Fibrosis (CF) is the most common life-limiting, autosomal recessive genetic disease affecting the U.S. population, and is due to mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. The consequence of the deltaF508CFTR mutation, the most common in the population, is a failure of the mutant CFTR protein to traffick correctly to the apical plasma membrane of epithelial cells in lung and elsewhere. A profoundly morbid consequence of an intrinsic proinflammatory phenotype occurs in the CF lung. We have designed and synthesized pyridinium salts that inhibit the formation of interleukin-8 in lung epithelial cells that act as a model of cystic fibrosis. These antagonists are amphiphilic pyridinium derivatives, and the mechanism of action is being explored. Members of this class of pyridinium derivatives have been found to block of neuronal calcium channels formed by aggregates of amyloid proteins. The P2X ion channels are receptor channels activated by extracellular ATP and mediate a number of potent and possibly important biological effects in the cardiovascular, inflammatory, and central nervous systems. Previous studies have shown that extracellular ATP can cause an ionic current in murine, rat and guinea pig cardiac ventricular myocytes. The receptor that mediates this current appears to be a P2X receptor, of which the P2X4 receptor is an important subunit. Activation of P2X receptors leads to the opening of a nonselective cation channel permeable to sodiumn, potassium, and calcium ions. The current is inward at negative membrane potentials, reverses near 0 mV, and becomes outward at positive potentials. The continuous activation of this receptor channel by endogenous extracellular ATP may assume an important biological function. This constant activation under the resting or negative membrane potentials would produce an inward current, whereas its activation during depolarized portions of the action potential should lead to an outward current. These currents represent a possible ionic mechanism by which the cardiac P2X channel achieves its biological effects. A potential biologically important role of the cardiac P2X receptor was suggested by the finding that cardiac myocyte-specific overexpression of the P2X4 receptor can rescue the hypertrophic and heart failure phenotype of the calsequestrin (CSQ) model of cardiomyopathy. However, little is known regarding regulation of the cardiac P2X receptor in cardiac hypertrophy or failure. Furthermore, it is not clear whether an increased activation of the endogenous P2X receptor channel is beneficial or harmful in the progression of heart failure. In collaboration with Dr. Bruce Liang (Univ.of Connecticut) we investigated the regulation of the P2X receptor-mediated ionic current and its potential role in heart failure using several novel nucleotide agonists. Chronic administration of a novel nucleotidase-resistant P2 receptor agonist MRS2339, which was capable of inducing this ionic current and devoid of any vasodilator action, reduced cardiac hypertrophy and increase lifespan. The data suggest that an important biological function of the cardiac P2X current is to favorably modulate the progression of cardiac hypertrophy and failure. The structure activity relationship of MRS2339 is currently being explored. The P2X7 receptor, a ligand gated ion channel that responds to ATP and other nucleotide derivatives, is involved in the inflammatory process. In the brain it occurs on microglial cells. Antagonists of the P2X7 receptor, based on tyrosine derivatives are being designed as functionalized congeners. In these antagonists, a reactive chain forms an extension of the Tyr side chain. Since the receptor likely consists of higher order bundles of multiple subunits, and we might expect more that one binding site for agonists or for antagonists to occur on each functional ion channel, we have designed dimers of these antagonists that still act as potent blockers of the actions of ATP.

囊性纤维化 (CF) 是影响美国人口的最常见的限制生命的常染色体隐性遗传病，由囊性纤维化跨膜调节因子 (CFTR) 基因突变引起。 deltaF508CFTR 突变（在人群中最常见）的后果是突变的 CFTR 蛋白无法正确运输到肺和其他部位上皮细胞的顶端质膜。 CF 肺中发生了内在促炎表型的严重病态后果。我们设计并合成了吡啶鎓盐，可抑制作为囊性纤维化模型的肺上皮细胞中白细胞介素 8 的形成。这些拮抗剂是两亲性吡啶鎓衍生物，其作用机制正在探索中。此类吡啶鎓衍生物的成员被发现可以阻断由淀粉样蛋白聚集体形成的神经元钙通道。 P2X 离子通道是由细胞外 ATP 激活的受体通道，在心血管、炎症和中枢神经系统中介导许多有效且可能重要的生物效应。先前的研究表明，细胞外 ATP 可以在小鼠、大鼠和豚鼠的心室肌细胞中引起离子电流。介导这种电流的受体似乎是P2X受体，其中P2X4受体是一个重要的亚基。 P2X 受体的激活导致可渗透钠离子、钾离子和钙离子的非选择性阳离子通道打开。膜电位为负时，电流向内，在 0 mV 附近反转，膜电位为正时，电流变为向外。内源性细胞外 ATP 对该受体通道的持续激活可能具有重要的生物学功能。这种在静息或负膜电位下的持续激活将产生内向电流，而其在动作电位的去极化部分期间的激活应导致外向电流。这些电流代表了心脏 P2X 通道实现其生物效应的可能离子机制。心肌细胞特异性 P2X4 受体过度表达可以挽救钙钙蛋白 (CSQ) 心肌病模型的肥厚和心力衰竭表型，这一发现表明心脏 P2X 受体具有潜在的重要生物学作用。然而，对于心脏肥大或衰竭中心脏 P2X 受体的调节知之甚少。此外，尚不清楚内源性 P2X 受体通道的激活增加对于心力衰竭的进展是有益还是有害。我们与 Bruce Liang 博士（康涅狄格大学）合作，使用几种新型核苷酸激动剂研究了 P2X 受体介导的离子电流的调节及其在心力衰竭中的潜在作用。长期服用新型抗核苷酸酶 P2 受体激动剂 MRS2339 能够诱导这种离子电流，并且没有任何血管舒张作用，可减少心脏肥大并延长寿命。数据表明，心脏 P2X 电流的一个重要生物学功能是有利地调节心脏肥大和衰竭的进展。 MRS2339的结构活性关系目前正在探索中。 P2X7 受体是一种配体门控离子通道，可响应 ATP 和其他核苷酸衍生物，参与炎症过程。 在大脑中，它发生在小胶质细胞上。基于酪氨酸衍生物的 P2X7 受体拮抗剂正在被设计为功能化同系物。在这些拮抗剂中，反应链形成酪氨酸侧链的延伸。由于受体可能由多个亚基的高阶束组成，并且我们可能期望在每个功能离子通道上出现不止一个激动剂或拮抗剂的结合位点，因此我们设计了这些拮抗剂的二聚体，它们仍然充当ATP 的作用。