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.
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