An updated assessment of the translational promise of G-protein-biased kappa opioid receptor agonists to treat pain and other indications without debilitating adverse effects.
An updated assessment of the translational promise of G-protein-biased kappa opioid receptor agonists to treat pain and other indications without debilitating adverse effects.
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DOI：
10.1016/j.phrs.2022.106091
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发表时间：
2022-03
影响因子：
9.3
通讯作者：
van Rijn RM
中科院分区：
文献类型：
--
作者：
French AR;van Rijn RM
Kappa阿片受体（κOR）激动剂缺乏临床使用的mu阿片受体（μOR）镇痛药的滥用倾向和呼吸抑制作用，被认为是更安全的替代品。然而，κOR激动剂本身具有有限的不良反应，包括厌恶、镇静和情绪影响，这阻碍了它们的临床转化。过去15年进行的研究表明，这些不良反应可能是由依赖于β-阻滞蛋白的不同细胞内信号通路的激活引起的，而G蛋白激活的下游信号通路产生抗伤感受。这导致了一种假设，即与传统的无偏倚激动剂相比，偏离β-抑制素信号的激动剂可以改善治疗窗口，并允许临床开发镇痛性g蛋白偏倚的κOR激动剂。鉴于最近关于g蛋白偏倚μOR激动剂的益处的争议，重新评估g蛋白偏倚κOR激动剂的治疗前景是及时的。在这里，我们回顾了临床前κOR研究的最新发现，并批判性地评估了g蛋白偏倚的κOR激动剂在上述每种不良反应中的治疗窗口。总的来说，我们发现g蛋白偏倚的κOR激动剂相对于无偏倚的激动剂通常具有更好的治疗窗口，尽管研究设计经常限制在这方面得出强有力的结论。然而，新开发的偏倚性κOR激动剂与最近设计的行为和分子工具相结合的稳定流动使κOR领域处于首要地位，使我们对κOR功能的理解取得重大进展，并履行将新一代偏倚性κOR激动剂转化为临床的承诺。
Kappa opioid receptor (κOR) agonists lack the abuse liability and respiratory depression effects of clinically used mu opioid receptor (μOR) analgesics and are hypothesized to be safer alternatives. However, κOR agonists have limiting adverse effects of their own, including aversion, sedation, and mood effects, that have hampered their clinical translation. Studies performed over the last 15 years have suggested that these adverse effects could result from activation of distinct intracellular signaling pathways that are dependent on β-arrestin, whereas signaling downstream of G protein activation produces antinociception. This led to the hypothesis that agonists biased away from β-arrestin signaling would have improved therapeutic windows over traditional unbiased agonists and allow for clinical development of analgesic G-protein-biased κOR agonists. Given a recent controversy regarding the benefits of G-protein-biased μOR agonists, it is timely to reassess the therapeutic promise of G-protein-biased κOR agonists. Here we review recent discoveries from preclinical κOR studies and critically evaluate the therapeutic windows of G-protein-biased κOR agonists in each of the adverse effects above. Overall, we find that G-protein-biased κOR agonists generally have improved therapeutic window relative to unbiased agonists, although frequently study design limits strong conclusions in this regard. However, a steady flow of newly developed biased κOR agonists paired with recently engineered behavioral and molecular tools puts the κOR field in a prime position to make major advances in our understanding of κOR function and fulfill the promise of translating a new generation of biased κOR agonists to the clinic.
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影响因子：
5
作者：
DiMattio KM;Ehlert FJ;Liu-Chen LY
通讯作者：
Liu-Chen LY
影响因子：
--
作者：
通讯作者：
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影响因子：
16.6
作者：
Che, Tao;English, Justin;Roth, Bryan L.
通讯作者：
Roth, Bryan L.
影响因子：
14.8
作者：
Carlezon, William A., Jr.;Chartoff, Elena H.
通讯作者：
Chartoff, Elena H.
影响因子：
7.3
作者：
De Marco, Rossella;Bedini, Andrea;Gentilucci, Luca
通讯作者：
Gentilucci, Luca