Oguri K, Yamada-Mori I, Shigezane J, Hirano T, Yoshimura H
Eur J Pharmacol. 1984 Jul 13;102(2):229-35. doi: 10.1016/0014-2999(84)90254-1.
The experiments concerned the effects of glucuronate or sulfate conjugation at the 6-position of nalorphine on the analgesic and antagonistic activities and also on the development of tolerance and physical dependence. Nalorphine-3-and 6-sulfate ester were synthesized for the first time. The analgesic effect of nalorphine-6-sulfate and -glucuronide was higher than that of nalorphine when assessed in the acetic acid writhing test. However, these 6-conjugates exhibited less potent agonistic activity in the test with guinea-pig ileum muscle strip and revealed no analgesic effect in the tail pinch test. The antagonistic activity of these 6-conjugates to morphine analgesia was lower on their s.c. injection, but higher on i.c.v. injection than that of nalorphine. The development of tolerance to the analgesia caused by nalorphine was not affected by the 6-modifications. Frequent withdrawal signs were seen in mice treated chronically with anlorphine-6-conjugates by challenging with naloxone while mice treated with nalorphine showed no such signs. This potent enhancing effect of 6-conjugation on the development of physical dependence was suggested to be also the case with morphine. These changes of potency due to conjugation were interpreted as due to the altered interaction with multiple opioid receptors.
这些实验涉及纳洛芬6位上葡萄糖醛酸或硫酸结合对镇痛和拮抗活性的影响，以及对耐受性和身体依赖性发展的影响。首次合成了纳洛芬-3-和6-硫酸酯。在醋酸扭体试验中评估时，纳洛芬-6-硫酸酯和-葡萄糖醛酸的镇痛效果高于纳洛芬。然而，这些6-结合物在豚鼠回肠肌条试验中表现出较弱的激动活性，并且在夹尾试验中未显示出镇痛效果。这些6-结合物对吗啡镇痛的拮抗活性在皮下注射时较低，但在脑室内注射时高于纳洛芬。6-修饰对纳洛芬引起的镇痛耐受性的发展没有影响。用纳洛酮激发时，长期用纳洛芬-6-结合物治疗的小鼠出现频繁的戒断症状，而用纳洛芬治疗的小鼠则没有这种症状。6-结合对身体依赖性发展的这种强效增强作用被认为吗啡也是如此。由于结合导致的效力变化被解释为与多种阿片受体相互作用的改变。
