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首页> 美国卫生研究院文献>other >Synthesis of 4567-Tetrahydrothieno32-cpyridines and Comparison with Their Isosteric 1234-Tetrahydroisoquinolines as Inhibitors of Phenylethanolamine N-Methyltransferase
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Synthesis of 4567-Tetrahydrothieno32-cpyridines and Comparison with Their Isosteric 1234-Tetrahydroisoquinolines as Inhibitors of Phenylethanolamine N-Methyltransferase

机译：4567-四氢噻吩并32-c吡啶的合成及其与等规1234-四氢异喹啉作为苯基乙醇胺N-甲基转移酶抑制剂的比较

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摘要

A series of substituted 4,5,6,7-tetrahydrothieno[3,2-c]pyridines (THTPs) was synthesized and evaluated for their human phenylethanolamine N-methyltransferase (hPNMT) inhibitory potency and affinity for the α2-adrenoceptor. The THTP nucleus was suggested as an isosteric replacement for the 1,2,3,4-tetrahydroisoquinoline (THIQ) ring system on the basis that 3-thienylmethylamine (>18) was more potent as an inhibitor of hPNMT and more selective towards the α2-adrenoceptor than benzylamine (>15). Although the isosterism was confirmed, with similar influence of functional groups and chirality in both systems on hPNMT inhibitory potency and selectivity, the THTP compounds proved, in general, to be less potent as inhibitors of hPNMT than their THIQ counterparts, with the drop in potency being primarily attributed to the electronic properties of the thiophene ring. A hypothesis for the reduced hPNMT inhibitory potency of these compounds has been formed on the basis of molecular modeling and docking studies using the X-ray crystal structures of hPNMT co-crystallized with THIQ-type inhibitors and S-adenosyl-l-homocysteine as a template.
机译：合成了一系列取代的4,5,6,7-四氢噻吩并[3,2-c]吡啶（THTP），并评估了其对人苯基乙醇胺N-甲基转移酶（hPNMT）的抑制能力和对α2-肾上腺素受体的亲和力。 THTP核被认为是1,2,3,4-四氢异喹啉（THIQ）环系统的等排替代物，因为3-噻吩甲胺（> 18 ）作为hPNMT抑制剂更有效对α2-肾上腺素受体的选择性要比苄胺（> 15 ）高。尽管已确认了等位性，但两个系统中的官能团和手性对hPNMT抑制效能和选择性的影响相似，但THTP化合物作为hPNMT抑制剂的效力总体上低于其THIQ对应物，且效力下降主要归因于噻吩环的电子性质。根据分子模型和对接研究，使用与THIQ型抑制剂和S-腺苷-1-同型半胱氨酸共结晶的hPNMT的X射线晶体结构，在分子建模和对接研究的基础上形成了这些化合物降低hPNMT抑制能力的假说。模板。

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