Grunewald G L, Ye Q, Sall D J, Criscione K R, Wise B
Department of Medicinal Chemistry, University of Kansas, Lawrence 66045.
Mol Pharmacol. 1989 Jan;35(1):93-7.
The conformational and steric aspects of binding to phenylethanolamine N-methyltransferase (PNMT; EC 2.1.1.28) for phenylethanolamine substrates and phenylethylamine inhibitors were probed with three conformationally defined analogues (11, 12, and 13) of phenylethylamine (1) and phenylethanolamine (6) containing the benzobicyclo[3.2.1]octane skeleton. The 2-aminotetralin (2AT) moiety in conformationally defined analogues 11, 12, and 13 exists in a half-chair conformation with an equatorial amino group. Although conformationally restricted phenylethylamine analogue 2AT (3, Ki = 6.8 microM) and conformationally restricted phenylethanolamine analogues (cis)- and (trans)-2-amino-1-tetralol (9, Km = 22 microM; Vmax = 0.15; 100 X Vmax/Km = 0.68; 10, Ki = 9.4 microM) are good ligands for PNMT, none of the analogues 11, 12, and 13 showed activity as a substrate of PNMT. The fact that 11 (Ki = 206 microM) is more potent than analogues 4 (Ki = 1296 microM) and 5 (Ki = 479 microM), with a half-boat 2AT moiety, suggests that PNMT preferentially binds the half-chair conformation of 2AT at the active site. This is consistent with previous findings that a fully extended conformation for the aminoethyl side chain of phenylethylamine inhibitors is optimal for PNMT binding. The reduced activity of 11, 12 (Ki = 1246 microM), and 13 (Ki = 3000 microM), compared with 2AT and (cis)- and (trans)-2-amino-1-tetralol (9 and 10) is consistent with a negative steric interference from the extra ethano bridge in 11, 12, and 13. The results from 11, 12, and 13, combined with previous findings, suggest that PNMT interacts better with relatively planar ligands.
利用三种含有苯并双环[3.2.1]辛烷骨架的苯乙胺（1）和苯乙醇胺（6）的构象确定类似物（11、12和13），研究了苯乙醇胺底物和苯乙胺抑制剂与苯乙醇胺N-甲基转移酶（PNMT；EC 2.1.1.28）结合的构象和空间方面。构象确定类似物11、12和13中的2-氨基四氢萘（2AT）部分以半椅式构象存在，氨基位于赤道平面。尽管构象受限的苯乙胺类似物2AT（3，Ki = 6.8 microM）和构象受限的苯乙醇胺类似物（顺式）-和（反式）-2-氨基-1-四氢萘酚（9，Km = 22 microM；Vmax = 0.15；100×Vmax/Km = 0.68；10，Ki = 9.4 microM）是PNMT的良好配体，但类似物11、12和13均未表现出作为PNMT底物的活性。11（Ki = 206 microM）比具有半船式2AT部分的类似物4（Ki = 1296 microM）和5（Ki = 479 microM）更有效，这一事实表明PNMT在活性位点优先结合2AT的半椅式构象。这与先前的研究结果一致，即苯乙胺抑制剂的氨基乙基侧链的完全伸展构象最适合PNMT结合。与2AT以及（顺式）-和（反式）-2-氨基-1-四氢萘酚（9和10）相比，11、12（Ki = 1246 microM）和13（Ki = 3000 microM）活性降低，这与11、12和13中额外的乙桥产生的负空间干扰一致。11、12和13的结果与先前的研究结果相结合，表明PNMT与相对平面的配体相互作用更好。
