Characterization of a Potential KOR/DOR Dual Agonist with No Apparent Abuse Liability via a Complementary Structure-Activity Relationship Study on Nalfurafine Analogues.
Characterization of a Potential KOR/DOR Dual Agonist with No Apparent Abuse Liability via a Complementary Structure-Activity Relationship Study on Nalfurafine Analogues.
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DOI：
10.1021/acschemneuro.2c00526
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发表时间：
2022-12-21
影响因子：
5
通讯作者：
Zhang, Yan
中科院分区：
文献类型：
--
作者：
Li, Mengchu;Stevens, David L.;Arriaga, Michelle;Townsend, E. Andrew;Mendez, Rolando E.;Blajkevch, Nadejda A.;Selley, Dana E.;Banks, Matthew L.;Negus, S. Stevens;Dewey, William L.;Zhang, Yan
发现不存在滥用责任的镇痛药对于应对美国的阿片类药物危机至关重要。在实现这一目标的许多策略中，靶向多个阿片受体似乎有望最大限度地减少这种不良副作用，同时实现合理的治疗方案。在了解纳芙拉芬的构效关系的过程中，我们发现了一种潜在的镇痛剂 NMF，它是一种滥用可能性最小的双重 KOR/DOR 激动剂。进一步的表征，包括主要体外 ADMET 研究（hERG 毒性、血浆蛋白结合、通透性和肝代谢）以及体内药效学和毒性分析（时程、滥用倾向、耐受性、戒断、呼吸抑制、体重和运动活性）进一步证实 NMF 是未来开发的有前途的候选药物。
Discovery of analgesics void of abuse liability is critical to battle the opioid crisis in the US. Among many strategies to achieve this goal, targeting more than one opioid receptor seems promising to minimize this unwanted side-effect while achieving a reasonable therapeutic profile. In the process of understanding the structure-activity relationship of nalfurafine, we identified a potential analgesic agent, NMF, as a dual KOR/DOR agonist with minimum abuse liability. Further characterizations, including primary in vitro ADMET studies (hERG toxicity, plasma protein binding, permeability and hepatic metabolism), and in vivo pharmacodynamic and toxicity profiling (time course, abuse liability, tolerance, withdrawal, respiratory depression, body weight, and locomotor activity) further confirmed NMF as a promising drug candidate for future development.
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影响因子：
2.7
作者：
Hartrick CT;Poulin D;Molenaar R;Hartrick A
通讯作者：
Hartrick A
影响因子：
5.1
作者：
Huang B;Gunta R;Wang H;Li M;Cao D;Mendez RE;Gillespie JC;Chen C;Huang LM;Liu-Chen LY;Selley DE;Zhang Y
通讯作者：
Zhang Y
影响因子：
7.4
作者：
Ackley, MA;Hurley, RW;Hammond, DL
通讯作者：
Hammond, DL
影响因子：
2.7
作者：
Andurkar, Shridhar V.;Reniguntala, Madhu Shaw J.;DeRuiter, Jack
通讯作者：
DeRuiter, Jack
DOI：
10.1016/j.jchromb.2006.04.031
发表时间：
2006-08-07
影响因子：
3
作者：
Buhrow, Sarah A.;Reid, Joel M.;Ames, Matthew M.
通讯作者：
Ames, Matthew M.