Grunewald G L, Ye Q, Kieffer L, Monn J A
Department of Medicinal Chemistry, University of Kansas, Lawrence 66045.
J Med Chem. 1988 Jan;31(1):169-71. doi: 10.1021/jm00396a026.
beta-Phenylethanolamines have long been known to be substrates for the enzyme that converts norepinephrine to epinephrine (phenylethanolamine N-methyltransferase, PNMT, EC 2.1.1.28). In an effort to determine which, if any, particular conformation of the aminoethyl side chain of phenylethanolamines is required for PNMT active site binding and catalysis, we have prepared and evaluated conformationally restricted phenylethanolamine analogues 8-10. The folded phenylethanolamine derivative 4-hydroxy-1,2,3,4-tetrahydroisoquinoline (8) is not a substrate and does not interact with the enzyme active site as an inhibitor as well as 1,2,3,4-tetrahydroisoquinoline (6). In the cyclic 2-aminotetralol systems, only cis-phenylethanolamine derivative 9 demonstrates activity as a PNMT substrate. The corresponding trans isomer 10 is not a substrate, in spite of enhanced active site interactions with respect to the parent analogue (2-aminotetralin, 4). Comparison of the inhibition constants for the folded (8,Ki = 175 microM) and extended (10,Ki = 9 microM) phenylethanolamine analogues strongly suggests that simultaneous binding of both the amino and hydroxyl functionalities to the PNMT active site requires an extended aminoethyl side chain conformation.
长期以来，人们一直知道β-苯乙醇胺是将去甲肾上腺素转化为肾上腺素的酶（苯乙醇胺N-甲基转移酶，PNMT，EC 2.1.1.28）的底物。为了确定苯乙醇胺氨基乙基侧链的哪种特定构象（如果有的话）是PNMT活性位点结合和催化所必需的，我们制备并评估了构象受限的苯乙醇胺类似物8-10。折叠的苯乙醇胺衍生物4-羟基-1,2,3,4-四氢异喹啉（8）不是底物，也不像1,2,3,4-四氢异喹啉（6）那样作为抑制剂与酶活性位点相互作用。在环状2-氨基四氢萘酚体系中，只有顺式苯乙醇胺衍生物9表现出作为PNMT底物的活性。相应的反式异构体10不是底物，尽管其与母体类似物（2-氨基四氢萘，4）相比与活性位点的相互作用增强。对折叠的（8，Ki = 175 microM）和伸展的（10，Ki = 9 microM）苯乙醇胺类似物的抑制常数进行比较，强烈表明氨基和羟基官能团同时与PNMT活性位点结合需要伸展的氨基乙基侧链构象。
