Ye Q H, Grunewald G L
Department of Medicinal Chemistry, University of Kansas, Lawrence 66045.
J Med Chem. 1989 Feb;32(2):478-86. doi: 10.1021/jm00122a032.
In a search for a selective inhibitor for the epinephrine synthesizing enzyme phenylethanolamine N-methyltransferase (PNMT; EC 2.1.1.28), phenolic 2-aminotetralins (12-15 as conformationally restricted analogues of tyramine) and phenolic benzobicyclo[3.2.1]octylamines (22-24 as conformationally defined analogues of tyramine) were used to gain information about the binding interactions of the catecholic hydroxyl groups in the natural substrate norepinephrine at the active site of PNMT. In addition, these analogues provided information about the effects of conformational flexibility on active-site interaction of the aminoethyl side chain in phenolic phenylethylamines that may aid in learning the manner in which norepinephrine binds at the active site of PNMT. Analogues 22-24 were synthesized by a nine-step sequence, in which a Friedel-Crafts type intramolecular cyclization was the key step in the construction of the benzobicyclo[3.2.1]octane skeleton. p-Tyramine (10, Ki = 294 microM) was more potent than phenylethylamine (1, Ki = 854 microM) but m-tyramine (9, Ki = 1250 microM) was less potent than phenylethylamine as an inhibitor of PNMT. Similarly, in the conformationally restricted and conformationally defined tyramine analogues (12-15 and 22-24, respectively), the analogues with the p-tyramine moiety (14, Ki = 4.7 microM; 23, Ki = 111 microM) bind to PNMT better than do the corresponding unsubstituted compounds (16, Ki = 6.8 microM; 25, Ki = 206 microM) while the analogues with the m-tyramine moiety (13, 15, 22, and 24) have a lower binding affinity than do 16 and 25. The greatly enhanced activity of the phenolic 2-aminotetralins (12-15) compared with m- and p-tyramine (9 and 10, respectively) is likely due to the restriction of the side-chain conformation. The conformationally defined analogues 22-24 were less active than the conformationally restricted ones, 12-15, although the low-energy half-chair conformation of 2-aminotetralin is defined in 22-24. The reduced activity of 22-24 compared with the activity of 12-15 is probably due to the steric hindrance from the extra bridging atoms in binding to PNMT. The interaction of the p-hydroxyl group of the tyramine moiety may involve hydrogen bonding since the corresponding methyl ethers show a greatly reduced affinity for the active site of PNMT (Ki = 34 and 389 microM for methoxy analogues 28 and 35, compared to Ki = 4.7 and 111 microM for the corresponding phenolic analogues 14 and 23).
为寻找肾上腺素合成酶苯乙醇胺N-甲基转移酶（PNMT；EC 2.1.1.28）的选择性抑制剂，使用酚类2-氨基四氢萘（12 - 15，作为酪胺的构象受限类似物）和酚类苯并双环[3.2.1]辛胺（22 - 24，作为酪胺的构象确定类似物）来获取有关天然底物去甲肾上腺素中儿茶酚羟基在PNMT活性位点的结合相互作用的信息。此外，这些类似物还提供了有关构象灵活性对酚类苯乙胺中氨基乙基侧链与活性位点相互作用的影响的信息，这可能有助于了解去甲肾上腺素在PNMT活性位点的结合方式。类似物22 - 24通过九步合成序列制备，其中傅克型分子内环化是构建苯并双环[3.2.1]辛烷骨架的关键步骤。对酪胺（10，Ki = 294 μM）作为PNMT抑制剂比苯乙胺（1，Ki = 854 μM）更有效，但间酪胺（9，Ki = 1250 μM）比苯乙胺效力更低。同样，在构象受限和构象确定的酪胺类似物（分别为12 - 15和22 - 24）中，具有对酪胺部分的类似物（14，Ki = 4.7 μM；23，Ki = 111 μM）与PNMT的结合比相应的未取代化合物（16，Ki = 6.8 μM；25，Ki = 206 μM）更好，而具有间酪胺部分的类似物（13、15、22和24）的结合亲和力低于16和25。与间酪胺和对酪胺（分别为9和10）相比，酚类2-氨基四氢萘（12 - 15）活性大大增强可能是由于侧链构象的限制。构象确定的类似物22 - 24比构象受限的类似物12 - 15活性低，尽管22 - 24中定义了2-氨基四氢萘的低能量半椅构象。与12 - 15的活性相比，22 - 24活性降低可能是由于与PNMT结合时额外桥连原子的空间位阻。酪胺部分的对羟基的相互作用可能涉及氢键，因为相应的甲基醚对PNMT活性位点的亲和力大大降低（甲氧基类似物28和35的Ki = 34和389 μM，而相应酚类类似物14和23的Ki = 4.7和111 μM）。
