DESIGN OF INHIBITORS OF EPINEPHRINE BIOSYNTHESIS

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后一步。 这种酶的水平增加，发现在压力期间， 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， 目前可用的抑制剂具有显著的副作用（例如， 是α 2-肾上腺素受体拮抗剂）。 因此，我们建议设计 通过绘制PNMT活性图， 具有一些精心选择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）。 解释苄胺类化合物抑制性结合差异的一个假说 和苯乙胺，并提出了多个芳香族化合物的问题， 检查环结合位点。 我们解决这些问题的方法 点涉及仔细的类似物设计，其次是基本的生化 和药理学评价。 此外，利用我们的新 提出了一种面向模拟设计的计算机图形系统。 一旦我们 划定了活性位点的地形，我们将设计类似物 它们是“量身定做”的，但活性可以忽略不计， 在其他生理相关的部位。 我们希望， 最终会产生一种全新的抗高血压药物

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.