DESIGN OF INHIBITORS OF EPINEPHRINE BIOSYNTHESIS

肾上腺素生物合成抑制剂的设计

• 批准号: 3346904
• 负责人: GARY L GRUNEWALD
• 金额: $ 16.95万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-06-01 至 1993-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3346904
• 关键词: alpha adrenergic receptor; antiadrenergic agents; antihypertensive agents; cardiovascular pharmacology; computer graphics /printing; conformation; drug adverse effect; drug design /synthesis /production; drug metabolism; drug screening /evaluation; enzyme inhibitors; enzyme mechanism; enzyme structure; epinephrine; ethanolamines; hormone inhibitor; hormone regulation /control mechanism; methyltransferase; norepinephrine; spontaneous hypertensive rat

Phenylethanolamine N-Methyltransferase (PNMT,E.C.2.1.1.28) is the enzyme that catalyzes the terminal step in the biosynthesis of epinephrine. Increased levels of this enzyme are found during periods of stress and in hypertension. Epinephrine has been implicated in a number of neuroregulatory processes in the brain. we have demonstrated that inhibitors of PNMT can lower blood pressure in spontaneously hypertensive rats; however, all of the inhibitors presently available show alpha 2-adrenergic receptor antagonism that could also produce some of the observed pharmacological effects. Therefore, we propose to design more selective inhibitors of this enzyme by mapping out the PNMT active site (1) with a few carefully selected structural and conformational probes (substrate analogues to probe the possibility of multiple aromatic ring binding sites and to probe the manner in which norepinephrine interacts at the active site of PNMT; multisubstrate inhibitors to enhance selectivity by occupying both the norepinephrine and AdoMet substrate sites, dead end inhibitors to probe the conformational requirements for binding of the ethanolamine side chain; and alternate substrate inhibitors to explore regional lipophilic effects upon binding), (2) with transferred NOE techniques to probe the conformation of ligands when bound to PNMT, and (3) by affinity labeling of amino acid residues at the active site. Results from all three sub- projects will be combined to refine a computer graphics model of the active site of PNMT, a model developed in our laboratories that (when integrated with a similar model to be developed for the alpha 2-adrenegic receptor) will allow the design and synthesis of a selective inhibitor of the enzyme. Such an inhibitor would be a useful pharmacological tool to probe the role played by epinephrine in the central nervous system.

苯乙醇胺N-甲基转移酶(PNMT，E.C.2.1.1.28) 酶催化生物合成的最后一步的酶 肾上腺素。这种酶的水平在 应激期和高血压期。肾上腺素一直是 牵涉到大脑中的许多神经调节过程。 我们已经证明了PNMT的抑制剂可以降低血液 自发性高血压大鼠的血压；然而，所有的 目前可用的抑制剂显示α2-肾上腺素能受体 对抗也可能产生一些观察到的 药理作用。因此，我们建议设计更多 通过绘制PNMT来选择该酶的抑制剂 活动地点(1)，有几个精心挑选的结构和 构象探针(底物类似物，用于探测 多个芳环结合位点的可能性和探索 去甲肾上腺素在去甲肾上腺素活性部位的相互作用方式 PNMT；多底物抑制剂通过以下方式提高选择性 同时占据去甲肾上腺素和ADOMet底物位点， 探索构象要求的死胡同抑制剂 乙醇胺侧链的结合；和替代底物 探索结合时局部亲脂效应的抑制剂)，(2) 用转移的NOE技术探测分子构象 与PNMT结合时的配体，以及(3)通过氨基的亲和标记 活性部位的酸残留物。结果来自所有三个小组- 项目将结合在一起，以完善计算机图形模型 我们实验室开发的模型--PNMT的活性部位 这(当与将为其开发的类似模型集成时 α2肾上腺素受体)将允许设计和合成 一种选择性的酶抑制剂。这样的抑制器将是 一种有用的药理学工具来探索 中枢神经系统中的肾上腺素。