Center for Organic and Medicinal Chemistry, Research Triangle Institute , P.O. Box 12194, Research Triangle Park, North Carolina 27709, United States.
J Med Chem. 2014 Apr 10;57(7):3140-7. doi: 10.1021/jm500184j. Epub 2014 Mar 26.
N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines (2a,b) are opioid receptor antagonists where the antagonist properties are not due to the type of N-substituent. In order to gain a better understanding of the contribution that the 3- and 4-methyl groups make to the pure antagonist properties of 2a,b, we synthesized analogues of 2a,b that lacked the 4-methyl (5a,b), 3-methyl (6a,b), and both the 3- and 4-methyl group (7a,b) and compared their opioid receptor properties. We found that (1) all N-methyl and N-phenylpropyl substituted compounds were nonselective opioid antagonists (2) all N-phenylpropyl analogues were more potent than their N-methyl counterparts, and (3) compounds 2a,b which have both a 3- and 4-methyl substituent, were more potent antagonists than analogues 5a,b, 6a,b, and 7a,b. We also found that the removal of 3-methyl substituent of N-methyl and N-phenylpropyl 3-methyl-4-(3-hydroxyphenyl)piperazines (8a,b) gives (4a,b), which are opioid antagonists.
N-取代的反式 3,4-二甲基-4-(3-羟基苯基)哌啶（2a,b）是阿片受体拮抗剂，其拮抗剂性质不是由于 N-取代基的类型。为了更好地了解 3-和 4-甲基对 2a,b 的纯拮抗剂性质的贡献，我们合成了缺乏 4-甲基（5a,b）、3-甲基（6a,b）和 3-和 4-甲基（7a,b）的 2a,b 的类似物，并比较了它们的阿片受体性质。我们发现：(1)所有 N-甲基和 N-丙基取代的化合物都是非选择性阿片受体拮抗剂；(2)所有 N-丙基类似物都比其 N-甲基类似物更有效；(3)具有 3-和 4-甲基取代基的化合物 2a,b 比类似物 5a,b、6a,b 和 7a,b 更有效。我们还发现，N-甲基和 N-丙基 3-甲基-4-(3-羟基苯基)哌嗪（8a,b）中 3-甲基取代基的去除会产生（4a,b），它是阿片受体拮抗剂。
