Grunewald G L, Ye Q H
Department of Medicinal Chemistry, University of Kansas, Lawrence 66045.
J Med Chem. 1988 Oct;31(10):1984-6. doi: 10.1021/jm00118a021.
Phenylethylamines and phenylethanolamines represent two major classes of ligands for the epinephrine synthesizing enzyme, phenylethanolamine N-methyltransferase (PNMT;EC 2.1.1.28). Phenylethylamines are usually competitive inhibitors and the isomers with the relative configuration as in (2S)-amphetamine (1) and (2S)-2-aminotetralin (3) are better inhibitors than their enantiomers. Phenylethanolamines are usually substrates of PNMT and the enzyme prefers the 1R isomers, such as (1R)-phenylethanolamine (5), in this class. Optically active norephedrines (7 and 8), norpseudoephedrines (9 and 10), and 2-amino-1-tetralols (13-16) were used to study the stereochemical requirements of phenylethanolamines for PNMT active site binding. Although the norephedrines (7 and 8) and the norpseudoephedrines (9 and 10) were poorer ligands for PNMT than were the 2-amino-1-tetralols (13-16), (1R,2S)-(-)-norephedrine (7) showed some activity as a PNMT substrate (Km = 1310 microM, Vmax = 0.22, 100 x Vmax/Km = 0.017). In the 2-amino-1-tetralols (13-16), the isomers with the 2S configuration (13 and 15) showed higher affinity to PNMT (13, Km = 4.5 microM; 15, Ki = 4.6 microM) and those with the 1R configuration (13 and 16) were substrates for the PNMT-catalyzed methyl transfer (13, Km = 4.5 microM, Vmax = 0.16, 100 x Vmax/Km = 3.6; 16, Km = 195 microM, Vmax = 0.12, 100 x Vmax/Km = 0.062); the combination of 1R and 2S configurations, such as in (1R,2S)-2-amino-1-tetralol (13), was required for a good substrate. These stereochemical requirements derived from the norephedrines (7 and 8), the norpseudoephedrines (9 and 10), and the 2-amino-1-tetralols (13-16) complement those for phenylethylamines (1-4) and for phenylethanolamines (5 and 6) and strongly suggest that phenylethylamine inhibitors bind to PNMT in the same orientation as do phenylethanolamine substrates.
苯乙胺类和苯乙醇胺类是肾上腺素合成酶——苯乙醇胺N-甲基转移酶（PNMT；EC 2.1.1.28）的两类主要配体。苯乙胺类通常是竞争性抑制剂，具有与(2S)-苯丙胺（1）和(2S)-2-氨基四氢萘（3）相同相对构型的异构体比它们的对映体是更好的抑制剂。苯乙醇胺类通常是PNMT的底物，并且该酶在此类中更倾向于1R异构体，例如(1R)-苯乙醇胺（5）。使用光学活性的去甲麻黄碱（7和8）、去甲伪麻黄碱（9和10）以及2-氨基-1-四氢萘醇（13 - 16）来研究苯乙醇胺类与PNMT活性位点结合的立体化学要求。尽管去甲麻黄碱（7和8）以及去甲伪麻黄碱（9和10）作为PNMT的配体比2-氨基-1-四氢萘醇（13 - 16）差，但(1R,2S)-(-)-去甲麻黄碱（7）表现出一定的作为PNMT底物的活性（Km = 1310 microM，Vmax = 0.22，100×Vmax/Km = 0.017）。在2-氨基-1-四氢萘醇（13 - 16）中，具有2S构型的异构体（13和15）对PNMT表现出更高的亲和力（13，Km = 4.5 microM；15，Ki = 4.6 microM），而具有1R构型的异构体（13和16）是PNMT催化甲基转移的底物（13，Km = 4.5 microM，Vmax = 0.16，100×Vmax/Km = 3.6；16，Km = 195 microM，Vmax = 0.12，100×Vmax/Km = 0.062）；良好的底物需要1R和2S构型的组合，例如(1R,2S)-2-氨基-1-四氢萘醇（13）。这些源自去甲麻黄碱（7和8）、去甲伪麻黄碱（9和10）以及2-氨基-1-四氢萘醇（13 - 16）的立体化学要求补充了苯乙胺类（1 - 4）和苯乙醇胺类（5和6）的要求，并有力地表明苯乙胺类抑制剂与PNMT的结合方向与苯乙醇胺类底物相同。
