MECHANISM & DESIGN OF NITRIC OXIDE SYNTHASE INACTIVATORS

机制

• 批准号: 2487877
• 负责人: RICHARD B SILVERMAN
• 金额: $ 21.67万
• 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 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2487877
• 关键词: active sites; adduct; amine oxidoreductase; arginine; chemical structure function; drug design /synthesis /production; enzyme inhibitors; enzyme mechanism; isozymes; nitric oxide synthase; peptide analog; stoichiometry

DESCRIPTION: Inhibition of nitric oxide (NO) synthase appears to be a viable approach for the blockage of neurotoxicity resulting from stroke, Huntington, and Alzheimer diseases, in the treatment of septic shock, long-term depression, and long-term potentiation, in protection against immune complex-induced vascular injury, and in the treatment of priapism. Five areas of research will be pursued directed at the design of new isoform-selective inhibitors, the design and mechanism of inactivation of new inactivators of nitric oxide synthase (NOS), and at one question of the catalytic mechanism of the enzyme. One class of new isoform-selective inhibitors is the N omega -alkyl-L-arginines; a series of these derivatives, based on the high selectivity the investigators recently found for N omega -propyl-L-arginine, will be synthesized and tested as inhibitors of the three isoforms of NOS. Another series proposed as isoform-selective inhibitors includes dipeptide and dipeptide esters, based on the high selectivity we found for the D-isomers of nitroarginine-containing peptides and peptide esters. Histidine- and N omega -alkyl-L-arginines- containing dipeptides and -dipeptide esters also will be made and tested for isoform selectivity. New inactivators proposed are analogs of N omega -allyl-L-arginines containing methyl and fluorine substituents to determine the effects of these substituents on the reactivity of the inactivator, on the partition ratio, and on isoform selectivity. Conformationally-rigid analogs of N omega -allyl-L-arginines will be prepared to determine conformational effects on inactivation and selectivity. Other potential inactivators include derivatives of N omega -propargyl-L-arginines, N-propargylguanidine, N-propargylornithine, and heterocyclic compounds containing an N-imidazolyl ornithine and the corresponding chlorinated analog. 2,2-Dichloro-1-iminoethyl-L-ornithine, the dichlorinated analog of the potent inactivator, N5-(1-iminoethyl)-L-ornithine, also will be prepared and tested. On the basis of the observation that hydrogen atom abstraction can occur at the alpha methylene of N omega - substituted arginines, N omega -cyclopropylmethyl-, 2-phenylcyclopropylmethyl-, and cubylmethyl analogs of arginine will be synthesized and tested. An attempt will be made to differentiate a hydrogen atom abstraction mechanism from an electron transfer mechanism for the oxidation of N omega -hydroxy-L-arginine by NOS.

描述：抑制一氧化氮（NO）合酶似乎是一种 可行的方法来阻塞中风引起的神经毒性， 亨廷顿和阿尔茨海默氏病治疗败血性休克， 长期抑郁症和长期增强，以防止 免疫复合物诱导的血管损伤，并在治疗priapism中。 将追求五个研究领域的研究领域 同工型选择性抑制剂，灭活的设计和机制 一氧化氮合酶（NOS）的新灭活剂，一个问题 酶的催化机制。 一类新的同工型选择 抑制剂是N omega-烷基-L-精氨酸；一系列这些衍生物， 基于高选择性，调查人员最近发现了N Omega - 丙酰 - L-精氨酸，将合成并测试为抑制剂 NOS的三种同工型。 提出的另一个系列是同工型选择性的 抑制剂包括基于高的二肽和二肽酯 我们发现含硝化精氨酸的肽的D-异构体 和肽酯。 组氨酸和N omega-烷基-L-精氨酸 - 含有 还将制造二肽和 - 二肽酯的同工型 选择性。 提出的新灭活因子是N Omega的类似物 - 含有甲基和氟取代基的亚甲基-L-精氨酸来确定 这些取代基对灭活剂反应性的影响， 分区比和同工型选择性。 构象辅助 N Omega-Alyl-L-精氨酸的类似物将准备确定 构象对失活和选择性的影响。 其他潜力 灭活因子包括n omega-propargyl-l-精氨酸的衍生物， N-丙甲甘甘尼丁，N-丙甲氨氨和杂环化合物 含有N-咪唑基鸟嘌呤和相应的氯化 类似物。 2,2-二氯-1-氨基乙基-l-氨基氨酸，二氯为类似物的类似物 也将准备有效​​的灭活剂N5-（1-氨基乙基）-L-雌雄氨酸 并经过测试。 根据观察到氢原子抽象的观察 可以发生在N omega的α-甲基 - 取代精氨酸，N omega - 环丙基甲基 - 2-苯基丙丙甲基甲基 - 和靠近的幼酰甲基类似物的类似物 精氨酸将合成和测试。 将尝试 将氢原子抽象机制与电子区分开 通过NOS氧化N omega-Hydroxy-L-精氨酸的转移机制。