Rafferty M F, Borchardt R T, Grunewald G L
J Med Chem. 1982 Oct;25(10):1204-8. doi: 10.1021/jm00352a021.
We investigated the directional nature of the bulk tolerance and hydrophobic binding in the aromatic ring binding region of the active site of norepinephrine N-methyltransferase (NMT) by comparing the substrate and inhibitor activities of m- and p-phenyl-substituted derivatives of amphetamine, phenylethanolamine, and alpha-methylbenzylamine. The para isomers of amphetamine and phenylethanolamine displayed significantly greater activities as inhibitor and substrate, respectively, than the meta isomers, which indicated that the bulk tolerance was near the para position. For benzylamines, the greatest inhibitory activity was observed for the meta isomer, demonstrating a significant difference in the binding requirements for phenylethylamines and benzylamines. These findings are consistent with a two-state model for the NMT active site that has been proposed elsewhere to account for its ability to bind both benzylamines and phenylethylamines in a fully extended side-chain conformation.
我们通过比较苯丙胺、苯乙醇胺和α-甲基苄胺的间位和对位苯基取代衍生物的底物和抑制剂活性，研究了去甲肾上腺素N-甲基转移酶（NMT）活性位点芳香环结合区域的体积耐受性和疏水结合的方向性。苯丙胺和苯乙醇胺的对位异构体分别作为抑制剂和底物表现出明显更高的活性，高于间位异构体，这表明体积耐受性接近对位。对于苄胺，间位异构体观察到最大的抑制活性，表明苯乙胺和苄胺的结合要求存在显著差异。这些发现与NMT活性位点的双态模型一致，该模型已在其他地方提出，以解释其在完全伸展的侧链构象中结合苄胺和苯乙胺的能力。
