DESIGN OF INHIBITORS OF EPINEPHRINE BIOSYNTHESIS

肾上腺素生物合成抑制剂的设计

• 批准号: 3346902
• 负责人: GARY L GRUNEWALD
• 金额: $ 19.08万
• 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/3346902
• 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; 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.

苯甲胺N-甲基转移酶（PNMT，E.C.2.1.1.28）IS 在生物合成中催化末端步骤的酶 肾上腺素。 在此期间发现该酶的水平增加 压力和高血压期。 肾上腺素已经过去了 与大脑中的许多神经调节过程有关。 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压力；但是，所有 目前可用的抑制剂显示α2-肾上腺素能受体 拮抗剂也可以产生某些观察到的 药理作用。 因此，我们建议设计更多 通过绘制PNMT的选择性抑制剂 活性位点（1），有一些精心选择的结构和 构象探针（底物类似物探测 多种芳族环结合位点的可能性并探测 去甲肾上腺素在活动位置相互作用的方式 pnmt;多底物抑制剂，以提高选择性 占据去甲肾上腺素和ADOMET底物位点， 死胡同抑制剂以探究构象要求 乙醇胺侧链的结合；和替代基板 抑制剂探索结合时区域亲脂性效应），（2） 使用转移的NOE技术来探测的构象 绑定到PNMT时配体，（3）通过氨基的亲和力标记 活性部位的酸残留物。 所有三个子的结果 项目将合并以完善计算机图形模型 PNMT的活跃站点，一种在我们的实验室中开发的模型 （当与类似模型集成以为 Alpha 2-二烯基受体）将允许设计和合成 酶的选择性抑制剂。 这样的抑制剂将是 一种有用的药理学工具，可以探究 中枢神经系统中的肾上腺素。