Grunewald G L, Dahanukar V H, Caldwell T M, Criscione K R
Department of Medicinal Chemistry, University of Kansas, Lawrence 66045, USA.
J Med Chem. 1997 Dec 5;40(25):3997-4005. doi: 10.1021/jm960235e.
7-(Aminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (SK&F 29661, 1) is a potent inhibitor of the enzyme phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28). In contrast to other inhibitors of PNMT, it is also highly selective toward PNMT in comparison with its affinity toward the alpha 2-adrenoceptor (PNMT Ki = 0.55 microM, alpha 2 Ki = 100 microM, selectivity [alpha 2 Ki/PNMT Ki] = 180). A diverse set of compounds was synthesized and evaluated to probe the role of the acidic hydrogen of the aminosulfonyl group of 1 in imparting this selectivity. Compounds were designed to investigate the effect on selectivity of the acidity of the NH group [the 7-N-methyl (compound 5) and 7-N-(p-chlorophenyl) (compound 4) derivatives of 1], the relative spatial position of the acidic hydrogen [7-(N-(methylsulfonyl)amino)-1,2,3,4-tetrahydroisoquinoline (6) and 7-((N-(methylsulfonyl)amino)methyl)-1,2,3,4-tetrahydroisoquinoline (8)], or the effect of the substitution of an acidic phenolic group for the aminosulfonyl moiety [1-(aminomethyl)-6-hydroxynaphthalene (23) and 8-hydroxy-1,2,3,4-tetrahydrobenz[h]isoquinoline (9)]. All of the compounds studied displayed lower affinity for PNMT than 1, and nine of the eleven compounds studied showed increased, rather than the desired decreased, affinity for the alpha 2-adrenoceptor. Specifically, compound 4, in which the aminosulfonyl NH group is more acidic than that in 1, showed greatly reduced selectivity on account of increased alpha 2-adrenoceptor affinity as compared to 1 (PNMT Ki = 2.6 microM, alpha 2 Ki = 6.3 microM, selectivity = 2.4). Compound 8, in which the acidic NH group is in the same region of space as that in 1, although the aminosulfonyl group is reversed with respect to the aromatic ring, showed poor PNMT affinity and modest alpha 2-adrenoceptor affinity (PNMT Ki = 330 microM, alpha 2 Ki = 18 microM, selectivity = 0.055). Compound 9, in which a phenolic group is in the same region of space as the acidic NH of 1, exhibited the best alpha 2-adrenoceptor affinity of any of the compounds studied (PNMT Ki = 0.98 microM, alpha 2 Ki = 0.078 microM, selectivity = 0.080). Results from this study suggest that the selectivity of 1 is not solely due to the presence of an acidic hydrogen on the 7-aminosulfonyl group of 1 but is likely also dependent on some other property (e.g. electron-withdrawing character) of the aminosulfonyl group.
7 -（氨磺酰基）-1,2,3,4 - 四氢异喹啉（SK&F 29661，1）是苯乙醇胺N - 甲基转移酶（PNMT，EC 2.1.1.28）的一种强效抑制剂。与其他PNMT抑制剂不同，相较于其对α2 - 肾上腺素能受体的亲和力，它对PNMT也具有高度选择性（PNMT的Ki = 0.55微摩尔，α2的Ki = 100微摩尔，选择性[α2 Ki/PNMT Ki] = 180）。合成并评估了一系列不同的化合物，以探究1的氨磺酰基酸性氢在赋予这种选择性方面的作用。设计这些化合物是为了研究NH基团酸度对选择性的影响[1的7 - N - 甲基（化合物5）和7 - N -（对氯苯基）（化合物4）衍生物]、酸性氢的相对空间位置[7 -（N -（甲基磺酰基）氨基）-1,2,3,4 - 四氢异喹啉（6）和7 -（（N -（甲基磺酰基）氨基）甲基）-1,2,3,4 - 四氢异喹啉（8）]，或者用酸性酚羟基取代氨磺酰基部分的影响[1 -（氨甲基）-6 - 羟基萘（23）和8 - 羟基 - 1,2,3,4 - 四氢苯并[h]异喹啉（9）]。所有研究的化合物对PNMT的亲和力都低于1，并且所研究的11种化合物中有9种对α2 - 肾上腺素能受体的亲和力增加，而不是如预期那样降低。具体而言，化合物4中氨磺酰基的NH基团比1中的酸性更强，与1相比，由于α2 - 肾上腺素能受体亲和力增加，其选择性大大降低（PNMT Ki = 2.6微摩尔，α2 Ki = 6.3微摩尔，选择性 = 2.4）。化合物8中酸性NH基团与1中的处于相同的空间区域，尽管氨磺酰基相对于芳香环是反转的，但其对PNMT的亲和力较差，对α2 - 肾上腺素能受体的亲和力适中（PNMT Ki = 330微摩尔，α2 Ki = 18微摩尔，选择性 = 0.055）。化合物9中酚羟基与1的酸性NH处于相同的空间区域，在所研究的任何化合物中它对α2 - 肾上腺素能受体的亲和力最佳（PNMT Ki = 0.98微摩尔，α2 Ki = 0.078微摩尔，选择性 = 0.080）。该研究结果表明，1的选择性不仅仅是由于1的7 - 氨磺酰基上存在酸性氢，还可能取决于氨磺酰基的一些其他性质（例如吸电子特性）。
