Novel Opioid Analgesics for the Development of Transdermal Opioid Patches That Possess Morphine-Like Pharmacological Profiles Rather Than Fentanyl: Possible Opioid Switching Alternatives Among Patch Formula.
Novel Opioid Analgesics for the Development of Transdermal Opioid Patches That Possess Morphine-Like Pharmacological Profiles Rather Than Fentanyl: Possible Opioid Switching Alternatives Among Patch Formula.
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DOI：
10.1213/ane.0000000000005954
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发表时间：
2022-05-01
影响因子：
5.7
通讯作者：
Hayashida M
中科院分区：
文献类型：
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作者：
Komatsu A;Miyano K;Nakayama D;Mizobuchi Y;Uezono E;Ohshima K;Karasawa Y;Kuroda Y;Nonaka M;Yamaguchi K;Iseki M;Uezono Y;Hayashida M
芬太尼透皮贴剂因其使用方便、安全、血药浓度稳定等优点而被广泛应用于重度疼痛的治疗。然而，患者通常对芬太尼产生耐受性，需要使用其他阿片类药物;丁丙诺啡透皮贴剂被广泛用作镇痛剂，尽管现有制剂不能提供与芬太尼透皮贴剂相当的镇痛效果。阿片类药物与阿片受体（OR）结合，激活G蛋白介导和β-抑制蛋白介导的通路。我们合成了具有高透皮吸收性的吗啡相关化合物（N1和N2），并与芬太尼和吗啡进行了比较，评价了它们的OR活性。在稳定表达μ-阿片受体（莫尔）、δ-阿片受体（DOR）和κ-阿片受体（KOR）的细胞中，使用CellKey和细胞内环磷酸腺苷（cAMP）测定法评估G蛋白介导的通路，同时使用β-抑制蛋白募集和受体内化测定法分析β-抑制蛋白介导的通路。此外，使用小鼠甩尾试验评价镇痛效果，并评价对芬太尼耐受小鼠的镇痛效果。在CellKey和cAMP测定中，N1和N2均显示出对莫尔的最高亲和力，并且充当DOR和KOR的完全激动剂以及部分激动剂。在β-arrestin和内化试验中，只有芬太尼作为完全激动剂; N1和N2作为莫尔的部分激动剂。在小鼠甩尾实验中，N1和N2显示出与芬太尼和吗啡相当的镇痛作用。在芬太尼耐受小鼠中，芬太尼显示出减弱的镇痛作用，而N1和N2以及吗啡保留了它们的镇痛作用。虽然N1和N2具有比芬太尼更高的透皮吸收性，但它们也具有与吗啡相当的镇痛作用，这表明它们可能是用于开发从芬太尼贴剂过渡的新型阿片类贴剂的有吸引力的化合物。
Transdermal fentanyl is widely used in the treatment of severe pain because of convenience, safety, and stable blood concentrations. Nevertheless, patients often develop tolerance to fentanyl, necessitating the use of other opioids; transdermal buprenorphine patch is widely used as an analgesic agent, though available formulation does not provide comparable analgesic effect as transdermal fentanyl patch. Opioids bind to the opioid receptor (OR) to activate both G protein–mediated and β-arrestin–mediated pathways. We synthesized morphine-related compounds with high transdermal absorbability (N1 and N2) and evaluated their OR activities pharmacologically in comparison with fentanyl and morphine. In cells stably expressing μ-opioid receptor (MOR), δ-opioid receptor (DOR), and κ-opioid receptor (KOR), G protein–mediated pathways were assessed using the CellKey and an intracellular cyclic adenosine monophosphate (cAMP) assay, while β-arrestin–mediated pathways were analyzed with β-arrestin recruitment and receptor internalization assays. Furthermore, analgesic effects were evaluated using a tail-flick test in mice, and the analgesic effect on fentanyl-tolerant mice was evaluated. In the CellKey and cAMP assays, both N1 and N2 showed the highest affinity for MOR and acted as full agonists as well as partial agonists for DOR and KOR. In the β-arrestin and internalization assays, only fentanyl acted as a full agonist; N1 and N2 acted as partial agonists of MOR. In the mouse tail-flick test, N1 and N2 showed analgesic effects equivalent to those of fentanyl and morphine. In fentanyl-tolerant mice, fentanyl showed a diminished analgesic effect, whereas N1 and N2 as well as morphine retained their analgesic effects. While N1 and N2 have higher transdermal absorbability than fentanyl, they also have analgesic effects comparable to those of morphine, suggesting that they may be attractive compounds for the development of novel opioid patches for transitioning from fentanyl patches.