Comparison of the binding of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines with their isosteric sulfonamides to the active site of phenylethanolamine N-methyltransferase
Comparison of the binding of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines with their isosteric sulfonamides to the active site of phenylethanolamine N-methyltransferase
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DOI：
10.1021/jm060466d
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发表时间：
2006-09-07
影响因子：
7.3
通讯作者：
Criscione, Kevin R.
中科院分区：
文献类型：
--
作者：
Grunewald, Gary L.;Seim, Mitchell R.;Criscione, Kevin R.
3-氟甲基-7-(N-取代的氨基磺酰基)-1,2,3,4-四氢异喹啉 (14、16 和 18-22) 是苯乙醇胺 N-甲基转移酶 (PNMT) 的高效选择性抑制剂。 3-氟甲基-7-(N-烷基氨基磺酰基)-1,2,3,4-四氢异喹啉（例如16）的分子模型研究表明，磺酰胺-NH-可以与Lys57的侧链形成氢键。然而，SAR 研究和人 PNMT (hPNMT) 与 7 复合物晶体结构的分析表明，磺酰胺氧，而不是磺酰胺 -NH-，与酶形成有利的相互作用。因此，我们假设用亚甲基取代磺酰胺-NH-可能会产生在 PNMT 上保留效力的化合物，并且会增加亲脂性，从而增加它们穿过血脑屏障的可能性。合成了一系列 3-氟甲基-7-磺酰基-1,2,3,4-四氢异喹啉 (23-30)，并评估了它们的 PNMT 抑制效力和对 R2-肾上腺素受体的亲和力。这些化合物与其等排磺酰胺（14、16 和 18-22）的比较表明，磺酰胺比相应的磺酰胺更具亲脂性，但效力较差。砜 24 (hPNMT K-i = 1.3 μM) 是该系列中最有效的化合物，与 R2 肾上腺素受体相比，对 PNMT 具有相当高的选择性，但 24 的效力不如相应的磺酰胺 16 (hPNMT K-i = 0.13 μM)。我们还报告了 hPNMT 与磺酰胺 15 复合物的晶体结构，从中鉴定出 hPNMT 活性位点内的潜在氢键受体，即 Asn39 的主链羰基氧。该残基与磺酰胺-NH-的相互作用可能是磺酰胺相对于砜的抑制效力增强的主要原因。
3-Fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines (14, 16, and 18-22) are highly potent and selective inhibitors of phenylethanolamine N-methyltransferase (PNMT). Molecular modeling studies with 3-fluoromethyl-7-(N-alkyl aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines, such as 16, suggested that the sulfonamide -NH-could form a hydrogen bond with the side chain of Lys57. However, SAR studies and analysis of the crystal structure of human PNMT (hPNMT) in complex with 7 indicated that the sulfonamide oxygens, and not the sulfonamide -NH-, formed favorable interactions with the enzyme. Thus, we hypothesized that replacement of the sulfonamide -NH-with a methylene group could result in compounds that would retain potency at PNMT and that would have increased lipophilicity, thus increasing the likelihood they will cross the blood brain barrier. A series of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines (23-30) were synthesized and evaluated for their PNMT inhibitory potency and affinity for the R2-adrenoceptor. A comparison of these compounds with their isosteric sulfonamides (14, 16, and 18-22) showed that the sulfones were more lipophilic but less potent than their corresponding sulfonamides. Sulfone 24 (hPNMT K-i = 1.3 mu M) is the most potent compound in this series and is quite selective for PNMT versus the R2-adrenoceptor, but 24 is less potent than the corresponding sulfonamide, 16 (hPNMT K-i = 0.13 mu M). We also report the crystal structure of hPNMT in complex with sulfonamide 15, from which a potential hydrogen bond acceptor within the hPNMT active site has been identified, the main chain carbonyl oxygen of Asn39. The interaction of this residue with the sulfonamide -NH-is likely responsible for much of the enhanced inhibitory potency of the sulfonamides versus the sulfones.