A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates.
A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates.
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DOI：
10.1126/scitranslmed.aar3483
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发表时间：
2018-08-29
影响因子：
17.1
通讯作者：
Ko MC
中科院分区：
文献类型：
--
作者：
Ding H;Kiguchi N;Yasuda D;Daga PR;Polgar WE;Lu JJ;Czoty PW;Kishioka S;Zaveri NT;Ko MC
处方阿片类药物的滥用、阿片类药物成瘾和过量强调了开发无成瘾有效药物治疗严重疼痛的迫切需要。阿片肽受体激动剂提供非常有效的疼痛缓解。然而，严重的副作用限制了它们在临床环境中的使用。痛觉肽/孤啡肽FQ肽（NOP）受体的激动剂已被证明可以调节MOP激动剂的抗痛觉和增强作用。在这里，我们报道了一种双功能NOP/MOP受体激动剂AT-121的发现和开发，它对NOP和MOP受体都具有部分激动剂活性。在非人灵长类动物中，AT-121抑制羟考酮的强化作用，发挥吗啡样镇痛作用。AT-121治疗不会引起阿片类药物通常相关的副作用，如呼吸抑制、滥用可能性、阿片类药物引起的痛觉过敏和身体依赖。我们在非人灵长类动物中的研究结果表明，NOP/MOP双功能激动剂在NOP和MOP激动剂活性的适当平衡下，可能提供安全有效的疼痛缓解和治疗处方阿片类药物滥用的双重治疗作用。小分子AT-121是疼痛肽和mu阿片肽受体的激动剂，在非人灵长类动物中介导无阿片相关副作用的镇痛。
Misuse of prescription opioids, opioid addiction, and overdose underscore the urgent need for developing addiction-free effective medications for treating severe pain. Mu opioid peptide (MOP) receptor agonists provide very effective pain relief. However, severe side effects limit their use in the clinical setting. Agonists of the nociceptin/orphanin FQ peptide (NOP) receptor have been shown to modulate the antinociceptive and reinforcing effects of MOP agonists. Here, we report the discovery and development of a bifunctional NOP/MOP receptor agonist, AT-121, which possesses partial agonist activity for both NOP and MOP receptors. AT-121 suppressed oxycodone’s reinforcing effects and exerted morphine-like analgesic effects in nonhuman primates. AT-121 treatment did not induce side effects commonly associated with opioids, such as respiratory depression, abuse potential, opioid-induced hyperalgesia, and physical dependence. Our results in nonhuman primates suggest that bifunctional NOP/MOP agonists with the appropriate balance of NOP and MOP agonist activity may provide a dual therapeutic action for safe and effective pain relief and treating prescription opioid abuse. The small molecule AT-121 is an agonist of nociceptin and mu opioid peptide receptors and mediates analgesia without opioid-associated side effects in non-human primates.
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影响因子：
16.6
作者：
Chen, Jun;Kang, Dawon;Xu, Jing;Lake, Marc;Hogan, James O.;Sun, Chaohong;Walter, Karl;Yao, Betty;Kim, Donghee
通讯作者：
Kim, Donghee
影响因子：
6
作者：
Degenhardt, Louisa;Charlson, Fiona;Vos, Theo
通讯作者：
Vos, Theo
影响因子：
8.8
作者：
Hayhurst, Christina J.;Durieux, Marcel E.
通讯作者：
Durieux, Marcel E.
影响因子：
3
作者：
Di Giannuario, A;Pieretti, S
通讯作者：
Pieretti, S
影响因子：
17.7
作者：
Brady, Kathleen T.;McCauley, Jenna L.;Back, Sudie E.
通讯作者：
Back, Sudie E.