Selective Inhibition of Neuronal Nitric Oxide Synthase

神经元一氧化氮合酶的选择性抑制

• 批准号: 6694089
• 负责人: RICHARD B SILVERMAN
• 金额: $ 27.44万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-04-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6694089
• 关键词: X ray crystallography; active sites; amine oxidoreductase; arginine; binding sites; chemical structure function; computer simulation; drug design /synthesis /production; enzyme inhibitors; enzyme mechanism; isozymes; nitric oxide synthase; nitro compounds; peptide analog; stoichiometry

DESCRIPTION (provided by applicant): Inhibition of neuronal nitric oxide synthase (NOS) appears to be a viable approach for the blockage of neurotoxicity resulting from stroke, Huntington, and Alzheimer diseases, and in the treatment of long-term depression and long-term potentiation. Seven general areas will be pursued directed at 1) synthesis and evaluation of conformationally-rigid peptidomimerics of Nomega-nitroarginine-Dbu and Nomega-nitroarginine-ornithine, our potent and selective nitric oxide synthase (NOS) inhibitors; 2) synthesis and evaluation of conformationally-rigid peptidomimetics of Nomega-nitroarginine-descarboxamides 3) synthesis and evaluation of peptidomimetics containing amide bond isosteres; 4) site-directed mutagenesis of groups that may bind to the sidechain amino group; 5) synthesis and evaluation of compounds to test the function of the nitro group in inhibition of NOS; 6) mechanisms of inactivation of NOS by known inactivators; and 7) X-ray crystal structures of inhibitor complexes with NOS and molecular modeling. The first series of compounds are 3- and 4-aminoproline- and 4- and 5-amino-2-pipecolic acid analogues of the selective dipeptides. Another series of compounds contains cyclic- and heterocyclic diamines, which will be substituted for straight-chain analogues we have made. Several series of compounds with isosteres of the amide bond of our selective inhibitors will be made containing beta- and gamma hydroxyethylene, ketomethylene, alkene, and alkane isosteres with both straight-chain and conformationally rigid (cyclic, aromatic, heteroaromatic) amines. To test our hypothesis for the function of the nitro group in selectivity, heteroaromatic analogues will be synthesized and evaluated for NOS inhibition. Previously we studied the inactivation of NOS by Nomega allylarginine and N-iminoethylomithine (MO). Structural and mechanistic studies will be carried out to support or modify our hypotheses for the inactivation mechanisms. Mechanisms of other compounds that appear to be structurally related to MO will be tested. A collaboration has been set up to carry out X-ray crystallography of our most potent and selective inhibitors bound to NOS to identify the important binding interactions, and the coordinates will be used for computer modeling studies using 3D-QSAR, DOCK, and GrowMol programs to identify new leads and modify the current ones.

描述（由申请人提供）：抑制神经元一氧化氮 合成酶（NOS）似乎是阻塞的可行方法 中风，亨廷顿和阿尔茨海默氏病产生的神经毒性，在 长期抑郁和长期增强的治疗。 七个一般区域将被指向1）合成和评估 Nomega-Nitroarininin-dbu的构象肽符合型肽症和 Nomega-Nitrochinine-Ernithine，我们的有效和选择性一氧化氮合酶 （NOS）抑制剂； 2）构象合成和评估 Nomega-Nitroarininin-Descarboxamides的肽仪3）合成和 评估含有酰胺键等质素的肽仪； 4）定向 可能与侧chain氨基群结合的组的诱变； 5）合成 并评估化合物以测试硝基在 抑制NOS； 6）已知灭活因子对NOS失活的机制； 7）抑制剂复合物与NOS和分子的X射线晶体结构 造型。第一个系列化合物是3和4-氨基氨基丙啉和4-，以及 选择性二肽的5-氨基-2-pipecolic酸类似物。另一个系列 化合物的含有环状和杂环二聚体，这将是 代替我们制作的直链类似物。几个系列 具有选择性抑制剂的酰胺键的等值化合物将是 包含β-和γ羟基乙烯，氯乙烯，烯烃和 具有直链和构象刚性的烷烃等值器（环状，循环， 芳香，异性）胺。测试我们的假设 选择性的硝基组，将合成异源类似物 并评估了NOS抑制作用。以前我们研究了NOS的失活 由Nomega Allylarninine和N-氨基乙基氨基氨酸（MO）。结构和 将进行机械研究以支持或修改我们的假设 失活机制。其他化合物的机制 在结构上与MO相关。已经建立了合作 进行我们最有效和选择性抑制剂的X射线晶体学 与NOS绑定以识别重要的结合相互作用，并 坐标将用于使用3D-QSAR，DOCK和 Growmol计划识别新线索并修改当前线索。