OPIOID AGONIST AND ANTAGONIST BIVALENT LIGANDS - THE RELATIONSHIP BETWEEN SPACER LENGTH AND SELECTIVITY AT MULTIPLE OPIOID RECEPTORS
OPIOID AGONIST AND ANTAGONIST BIVALENT LIGANDS - THE RELATIONSHIP BETWEEN SPACER LENGTH AND SELECTIVITY AT MULTIPLE OPIOID RECEPTORS
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DOI：
10.1021/jm00160a010
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发表时间：
1986-10-01
影响因子：
7.3
通讯作者：
TAKEMORI, AE
中科院分区：
文献类型：
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作者：
PORTOGHESE, PS;LARSON, DL;TAKEMORI, AE
合成了含有连接到不同长度的间隔基上的羟莫法明或纳曲胺药效团的二价配体，并评价了它们在µ，kappa的选择性。和.德尔塔。阿片受体。羟甲基甲胺二价配体(1-8)表现为MU。电刺激豚鼠回肠纵肌准备(GPI)激动剂。在这些序列中提供最大激动剂活性的间隔基总共包含四个甘氨酰单元(n=2)。与Guriea猪脑膜的结合研究显示，在.MU处有定性相似的分布。受体作为间隔区长度的函数。还有，德尔塔。受体选择性随着间隔基的加长而增加。纳曲胺二价配体(9-13)能有效拮抗MU。受体激动剂吗啡在GPI中的最佳间隔长度(n=2)与激动剂系列中的相同。而乙基酮唑类药物的峰值拮抗作用为Kappa。受体激动剂，与含有最短间隔的二价配体9发生(n=0)，发现9是最具选择性的kappa。系列赛中的对手。而受体结合大致与kappa相似。在GPI中的拮抗活性，在MU处没有观察到结合与拮抗活性之间的相关性。阿片受体。讨论了这些结果的可能意义。
Bivalent ligands containing the oxymorphamine or naltrexamine pharmacophores connected to spacers of varying length were synthesized and evaluated for their selectivity at .mu., .kappa. and .delta. opioid receptors. The oxymorphamine bivalent ligands (1-8) behaved as .mu. agonists on the electrically sitmulated guinea pig ileum longitudinal muscle preparation (GPI). The spacer that conferred peak agonist activity in these series contains a total of four glycyl units (n = 2). Binding studies with guniea pig brain membranes showed a qualitatively similar profile at .mu. receptors as a function of spacer length. Also, .delta. receptor selectivity increased as the spacer was lengthened. The naltrexamine bivalent ligands (9-13) effectively antagonized the .mu. receptor agonist morphine in the GPI at the same optimal spacer length (n = 2) as in the agonist series. However, the peak antagonism of ethylketazocine, a .kappa. receptor agonist, occurred with the bivalent ligand 9 containing the shortest spacer (n = 0), and it was found that 9 is the most selective .kappa. antagonist in the series. While receptor binding roughly parallels that of .kappa. antagonist activity in the GPI, no correlation between binding and antagonist activity was observed at .mu. opioid receptors. The possible significance of these results is discussed.