Research Triangle Institute , P.O. Box 12194, Research Triangle Park, North Carolina 27709-2194, United States.
Naval Research Laboratory, Code 6910, 455 Overlook Avenue, Washington, D.C. 20375, United States.
J Org Chem. 2016 Nov 4;81(21):10383-10391. doi: 10.1021/acs.joc.6b01366. Epub 2016 Aug 2.
In order to gain additional information concerning the active conformation of the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (1) class of opioid receptor antagonists, procedures were developed for the synthesis of structurally rigid N-substituted-6-(3-hydroxyphenyl)3-azabicyclo[3.1.0]hexane and 3-methyl-4-(3-hydroxyphenyl)-4-azabicyclo[4.1.0]heptanes. Evaluation of the conformationally constrained series in a [S]GTPγS assay showed that structural rigid compounds having the 3-hydroxyphenyl group locked in the piperidine equatorial orientation had potencies equal to or better than similar compounds having more flexible structures similar to 1. The studies of the rigid compounds also suggested that the 3-methyl group present in compound 1 type antagonists may not be necessary for their pure opioid antagonist properties.
为了获得有关 N-取代反式-3,4-二甲基-4-(3-羟基苯基)哌啶(1)类阿片受体拮抗剂的活性构象的附加信息,开发了用于合成结构刚性的 N-取代-6-(3-羟基苯基)-3-氮杂双环[3.1.0]己烷和 3-甲基-4-(3-羟基苯基)-4-氮杂双环[4.1.0]庚烷的程序。在[S]GTPγS 测定中对构象受约束的系列进行评估表明,具有 3-羟基苯基基团锁定在哌啶赤道取向的结构刚性化合物的效力与具有更灵活结构类似于 1 的类似化合物相当或更好。刚性化合物的研究还表明,化合物 1 型拮抗剂中存在的 3-甲基基团对于其纯阿片受体拮抗剂特性可能不是必需的。