U-50,488: a selective and structurally novel non-Mu (kappa) opioid agonist.
U-50,488: a selective and structurally novel non-Mu (kappa) opioid agonist.
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发表时间：
1983
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通讯作者：
P. Vonvoigtlander;R. Lahti;J. H. Ludens
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作者：
P. Vonvoigtlander;R. Lahti;J. H. Ludens
U-50,488（反式-3,4-二氯-N-甲基-N-[2-(1-吡咯烷基）环己基]-苯乙酰胺）在小鼠和大鼠的多种（热、压力和刺激）测定中显示出镇痛作用。纳洛酮和 MR-2266 可以阻断这种镇痛作用；因此它是由阿片受体介导的。然而，与吗啡镇痛相比，U-50,488 镇痛的纳洛酮和 MR-2266 pA2 值分别低得多和高得多。同样，虽然吗啡和 U-50,488 镇痛药均产生耐受性，但这些药物之间不存在交叉耐受性，并且 U-50,488 不会引起吗啡型身体依赖性。这些观察结果表明，不同的阿片受体介导吗啡和 U-50,488 的镇痛作用。 U-50,488 的作用似乎是由所谓的 kappa 阿片受体介导的。与 U-50,488 相比，其他著名的 kappa 阿片类激动剂表现出不同程度的 mu 激动剂（酮他佐辛和乙基酮环佐辛）和麻醉拮抗剂（布马佐辛）活性。因此，U-50,488 是一种更具选择性的 κ 激动剂。这一结论得到了结合研究的进一步支持；在所有测试的化合物中，[3H]乙基酮环佐辛结合的 U-59,488 置换独特地不被高浓度的二氢吗啡阻断。除了镇痛作用外，这种选择性 kappa 激动剂还会引起阿片受体介导的镇静、利尿和皮质类固醇升高。 U-50,488 是研究对比 kappa 和 mu 阿片受体介导作用的有用工具。
U-50,488 (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide) displays analgesic actions in a variety (thermal, pressure and irritant) of assays in mice and rats. Naloxone and MR-2266 block this analgesic effect; thus it is mediated by opioid receptors. However, when compared to morphine analgesia, the naloxone and MR-2266 pA2 values for U-50,488 analgesia were much lower and higher, respectively. Likewise, although tolerance occurs to both morphine and U-50,488 analgesia, there was no cross-tolerance between these drugs, and U-50,488 does not cause morphine-type physical dependence. These observations suggest that different opioid receptors mediate the analgesic effects of morphine and U-50,488. The effects of U-50,488 appear to be mediated by the so-called kappa opioid receptor. In contrast to U-50,488, other reputed kappa opioid agonists displayed varying degrees of mu agonist (ketazocine and ethylketocyclazocine) and narcotic antagonist (bremazocine) activities. Thus U-50,488 is a more selective kappa agonist. This conclusion is further supported by binding studies; of all compounds tested, U-59,488 displacement of [3H]ethylketocyclazocine binding was uniquely not blocked by high concentrations of dihydromorphine. In addition to analgesia, this selective kappa agonist also causes opioid receptor-mediated sedation, diuresis and corticosteroid elevations. U-50,488 is a useful tool for studying contrasting kappa and mu opioid receptor-mediated effects.