DESIGN OF INHIBITORS OF EPINEPHRINE BIOSYNTHESIS

肾上腺素生物合成抑制剂的设计

• 批准号: 3346900
• 负责人: GARY L GRUNEWALD
• 金额: $ 11.25万
• 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 1988-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3346900
• 关键词: antiadrenergic agents; antihypertensive agents; benzylamines; cardiovascular pharmacology; computer graphics /printing; conformation; drug adverse effect; drug design /synthesis /production; drug metabolism; drug screening /evaluation; enzyme structure; epinephrine; ethanolamines; hormone regulation /control mechanism; methyl group

Phenylethanolamine N-Methyltransferase (PNMT, E.C. 2.1.1.28) is the enzyme which catalyzes the terminal step in the biosynthesis of epinephrine. Increased levels of this enzyme are found during periods of stress and in hypertension. We have demonstrated that inhibitors of this enzyme can lower blood pressure in spontaneously hypertensive rats; however, all of the inhibitors presently available have significant side effects (e.g. all are Alpha2-adrenoreceptor antagonists). Therefore, we propose to design more selective inhibitors of this enzyme by mapping out the PNMT active site with a few carefully selected structural and conformational probes (substrate analogues, dead end inhibitors, alternate substrate inhibitors). An hypothesis to explain the inhibitory binding differences of benzylamines and phenylethylamines is proposed, and the question of multiple aromatic ring binding sites is examined. Our approach toward addressing these points involves careful analogue design followed by essential biochemical and pharmacological evaluations. In addition, the utilization of our new computer graphics system toward analogue design is proposed. Once we have delineated the topography of the active site, we will design analogues which are "tailor made" to fit into it, but which have negligible activity at other physiologically-relevant sites. It is our hope that this approach will eventually lead to an entirely new class of antihypertensive agents.

苯乙醇胺 N-甲基转移酶 (PNMT, E.C. 2.1.1.28) 是酶 它催化肾上腺素生物合成的最终步骤。 在压力期间和在工作中发现这种酶的水平增加 高血压。 我们已经证明这种酶的抑制剂可以 降低自发性高血压大鼠的血压；然而，所有的 目前可用的抑制剂具有显着的副作用（例如所有 是α2-肾上腺素受体拮抗剂）。 因此，我们建议设计 通过绘制 PNMT 活性，对该酶更具选择性的抑制剂 具有一些精心挑选的结构和构象探针的位点 （底物类似物、死端抑制剂、替代底物抑制剂）。 解释苯甲胺抑制结合差异的假设 提出了苯乙胺，以及多重芳香族的问题 检查环结合位点。 我们解决这些问题的方法 要点涉及仔细的模拟设计，然后是必要的生化 和药理评价。 此外，利用我们的新 提出了面向模拟设计的计算机图形系统。 一旦我们有 描绘了活性位点的地形，我们将设计类似物 它们是“量身定制”以适应它的，但其活性可以忽略不计 在其他生理相关部位。 我们希望这种方法 最终将产生一类全新的抗高血压药物。