Grunewald G L, Sall D J, Monn J A
Department of Medicinal Chemistry, University of Kansas, Lawrence 66045.
J Med Chem. 1988 Apr;31(4):824-30. doi: 10.1021/jm00399a024.
1,2,3,4-Tetrahydroisoquinoline (THIQ) and aryl-substituted derivatives of THIQ are potent inhibitors of the enzyme that catalyzes the formation of epinephrine--phenylethanolamine N-methyltransferase (PNMT, E.C. 2.1.1.28). In previous studies, we found that substitution of the 3-position of THIQ with a methyl group resulted in enhanced activity as an inhibitor for 3-methyl-THIQ with respect to THIQ itself. To more fully delineate this region of the PNMT active site, we have synthesized and evaluated other 3-substituted THIQ analogues that vary in both steric and electronic character. Extension of the methyl side chain in 8 by a single methylene unit results in diminished potency for 3-ethyl-THIQ, suggesting that this zone of the active site is spatially compact; furthermore, the region of steric intolerance may be located principally on only "one side" of the 3-position of bound THIQs, since the carbonyl containing (bent) analogues 3-(methoxycarbonyl)-THIQ and 3-(aminocarbonyl)-THIQ are much less capable of forming a strong enzyme-inhibitor dissociable complex compared to straight-chain derivatives possessing a similar steric component. The good activity of 3-(hydroxymethyl)-THIQ as a PNMT inhibitor cannot be explained solely by steric tolerance for this side chain. We believe that an active-site amino acid residue capable of specific (i.e., hydrogen bond) interactions is located in close proximity to the 3-position of bound THIQs and that association of the OH functionality with this active-site residue results in the enhanced in vitro potency of this analogue (Ki = 2.4 microM) compared to that of THIQ (Ki = 10.3 microM). Incorporation of a hydroxymethyl substituent onto the 3-position of the potent PNMT inhibitor 7,8-dichloro-THIQ (SKF 64139, Ki = 0.24 microM) did not result in the same enhancement in inhibitor potency for 17 (Ki = 0.38 microM). This result suggests that simultaneous binding in an optimal orientation of the aromatic halogens, secondary amine, and side-chain hydroxyl functionalities to the PNMT active site is not allowed in this analogue.
1,2,3,4-四氢异喹啉（THIQ）及其芳基取代衍生物是催化肾上腺素形成的酶——苯乙醇胺N-甲基转移酶（PNMT，E.C. 2.1.1.28）的有效抑制剂。在先前的研究中，我们发现用甲基取代THIQ的3位会导致3-甲基-THIQ相对于THIQ本身作为抑制剂的活性增强。为了更全面地描绘PNMT活性位点的这个区域，我们合成并评估了其他在空间和电子特性上有所不同的3-取代THIQ类似物。在8中甲基侧链延伸一个亚甲基单元会导致3-乙基-THIQ的效力降低，这表明活性位点的这个区域在空间上是紧凑的；此外，空间不容纳区域可能主要仅位于结合的THIQs的3位的“一侧”，因为与具有相似空间成分的直链衍生物相比，含羰基（弯曲）的类似物3-（甲氧基羰基）-THIQ和3-（氨基羰基）-THIQ形成强的酶-抑制剂可解离复合物的能力要弱得多。3-（羟甲基）-THIQ作为PNMT抑制剂的良好活性不能仅通过对该侧链的空间耐受性来解释。我们认为，一个能够进行特异性（即氢键）相互作用的活性位点氨基酸残基位于与结合的THIQs的3位紧密相邻的位置，并且OH官能团与该活性位点残基的缔合导致该类似物（Ki = 2.4 microM）与THIQ（Ki = 10.3 microM）相比在体外效力增强。在强效PNMT抑制剂7,8-二氯-THIQ（SKF 64139，Ki = 0.24 microM）的3位引入羟甲基取代基并没有导致17（Ki = 0.38 microM）的抑制剂效力有相同程度的增强。这个结果表明，在该类似物中，芳香族卤素、仲胺和侧链羟基官能团不能以最佳取向同时结合到PNMT活性位点。
