Ong H H, Anderson V B, Wilker J C
J Med Chem. 1978 Aug;21(8):758-63. doi: 10.1021/jm00206a008.
A series of 5-aryl-2-azabicyclo[3.2.1]octanes II has been synthesized and evaluated for analgetic agonist-antagonist activity. These compounds can be regarded as five-membered, conformationally more rigid analogues of the potent agonist-antagonist (-)-5-(3-hydroxyphenyl)-2-methylmorphan (I). Several of these compounds have demonstrated marked analgesic potency comparable to morphine in the mouse writhing assay. Structure-activity correlations, generated by varying N-substitution and O-acetylation of the phenolic function, seem to indicate that optimum activity is associated with an arylethyl side chain attached to the basic nitrogen. Among the most interesting compounds in this series are the phenethyl analogue 31 and its O-acetate 39; the former shows the profile of a well-balanced analgetic-antagonist virtually devoid of physical dependence liability as demonstrated in the rat infusion test.
已经合成了一系列5-芳基-2-氮杂双环[3.2.1]辛烷II，并对其镇痛激动剂-拮抗剂活性进行了评估。这些化合物可被视为强效激动剂-拮抗剂（-）-5-（3-羟基苯基）-2-甲基吗啡（I）的五元、构象更刚性的类似物。其中几种化合物在小鼠扭体试验中显示出与吗啡相当的显著镇痛效力。通过改变酚羟基的N-取代和O-乙酰化产生的构效关系似乎表明，最佳活性与连接在碱性氮上的芳基乙基侧链有关。该系列中最有趣的化合物包括苯乙基类似物31及其O-乙酸酯39；前者显示出一种平衡良好的镇痛-拮抗剂特征，在大鼠输注试验中几乎没有身体依赖性倾向。
