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）是影响美国人群的最常见的生命遗传遗传遗传疾病，是由于囊性纤维化跨膜调节剂（CFTR）基因的突变。 Deltaf508CFTR突变是人群中最常见的结果，是突变CFTR蛋白的失败，无法正确运输到肺和其他地方的上皮细胞的顶质膜。内在促炎表型的严重病态后果发生在CF肺中。我们已经设计和合成了吡啶丁盐，这些吡啶盐盐抑制了肺上皮细胞中白介素8的形成，该细胞充当囊性纤维化模型。这些拮抗剂是两亲性吡啶衍生物，正在探索作用机理。已经发现，这类吡啶衍生物的成员可以阻止淀粉样蛋白聚集体形成的神经元钙通道。 P2X离子通道是通过细胞外ATP激活的受体通道，并介导心血管，炎症和中枢神经系统中的许多有效且可能重要的生物学作用。先前的研究表明，细胞外ATP可能导致鼠，大鼠和豚鼠心室心肌细胞的离子电流。介导该电流的受体似乎是P2X受体，其中P2X4受体是重要的亚基。 P2X受体的激活导致向钠，钾和钙离子渗透的非选择性阳离子通道的打开。电流是在负膜电位下向内向内的，逆转接近0 mV，并以正势向外变。内源性细胞外ATP对该受体通道的连续激活可能会假定重要的生物学功能。在静息或负膜电位下的这种恒定激活将产生内向电流，而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通道实现其生物学作用的可能的离子机制。通过发现，心肌细胞特异性的过表达P2X4受体可以挽救心肌病的肥大和心力衰竭表型，这表明心脏肌细胞特异性的过表达（CSQ）心脏肌病模型的肥大和心力衰竭表型。然而，关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受体通道的激活是否增加对心力衰竭的进展是有益或有害的。与Bruce Liang博士（康涅狄格大学）合作，我们研究了P2X受体介导的离子电流的调节及其在心力衰竭中使用几种新型核苷酸激动剂在心力衰竭中的潜在作用。长期给予一种新型的核苷酸酶抗性P2受体激动剂MRS2339，该抗核苷酸受体激动剂能够诱导这种离子电流并没有任何血管舒张作用，减少了心脏肥大并增加了寿命。数据表明，心脏P2X电流的重要生物学功能是有利地调节心脏肥大和衰竭的进展。目前正在探索MRS2339的结构活动关系。 P2X7受体是对ATP和其他核苷酸衍生物反应的配体门控离子通道，参与了炎症过程。 在大脑中，它发生在小胶质细胞上。基于酪氨酸衍生物的P2X7受体的拮抗剂正在设计为功能化的同类物。在这些拮抗剂中，一个反应链形成了Tyr侧链的延伸。由于受体可能由多个亚基的高阶束组成，我们可能会期望更多的激动剂或拮抗剂发生在每个功能离子通道上的一个结合位点，因此我们设计了这些拮抗剂的二聚体，这些拮抗剂仍然是ATP作用的有效阻断者。