Lee Alex S, Tiwari Suchi, Bishop Isabel, Matossian Vartan, Romaneschi Nicole, Miyazaki Takahiro, VanderVeen Laurie, Zalevsky Jonathan, DeFea Kathryn, Cahill Catherine M, Walwyn Wendy M
Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, United States.
Nektar Therapeutics, San Francisco, CA, United States.
Front Pain Res (Lausanne). 2021 Aug 23;2:695962. doi: 10.3389/fpain.2021.695962. eCollection 2021.
Mu opioid receptor (MOPr) agonists are well-known and frequently used clinical analgesics but are also rewarding due to their highly addictive and often abusive properties. This may lead to opioid use disorder (OUD) a disorder that effects millions of people worldwide. Therefore, novel compounds are urgently needed to treat OUD. As opioids are effective analgesics and OUD often occurs in conjunction with chronic pain, these novel compounds may be opioids, but they must have a low abuse liability. This could be mediated by diminishing or slowing blood-brain barrier transport, slowing target receptor binding kinetics, and showing a long half-life. NKTR-181 is a PEGylated oxycodol and a MOPr agonist that has slowed blood-brain barrier transport, a long half-life, and diminished likeability in clinical trials. In this study, we examined the signaling and behavioral profile of NKTR-181 in comparison with oxycodone to determine whether further therapeutic development of this compound may be warranted. For this preclinical study, we used a number of and assays. The signaling profile of NKTR-181 was determined by the electrophysiological assessment of MOPr-Ca channel inhibition in the nociceptive neurons of rodent dorsal root ganglia. Heterologous cell-based assays were used to assess biased agonism and receptor trafficking. Different rodent behavioral models were used to define the NKTR-181-induced relief of effective and reflexive nociception and drug-seeking behavior as assessed by an intravenous self-administration (IVSA) of NKTR-181. We found that NKTR-181 and oxycodone are partial agonists in G-protein signaling and Ca channel inhibition assays and promote limited MOPr desensitization. However, NKTR-181 inhibits Ca channels by a different mechanism than oxycodone and induces a different pattern of arrestin recruitment. In addition, NKTR-181 has a slower receptor on-rate and a slower rate of Ca channel coupling than oxycodone. This signaling profile is coupled with a slower onset of antinociception and limited drug-seeking behavior in comparison with oxycodone. Together with its known long half-life and slow blood-brain barrier transport, these data suggest that NKTR-181 could be further studied as a pharmacotherapeutic treatment modality for OUD.
μ阿片受体（MOPr）激动剂是广为人知且常用的临床镇痛药，但因其具有高度成瘾性且常被滥用的特性，也会带来奖赏效应。这可能导致阿片类物质使用障碍（OUD），该疾病影响着全球数百万人。因此，迫切需要新型化合物来治疗OUD。由于阿片类药物是有效的镇痛药，且OUD常与慢性疼痛同时出现，这些新型化合物可能是阿片类药物，但它们的滥用可能性必须很低。这可以通过减少或减缓血脑屏障转运、减缓靶受体结合动力学以及显示出较长的半衰期来实现。NKTR - 181是一种聚乙二醇化羟考酮，也是一种MOPr激动剂，它减缓了血脑屏障转运，具有较长的半衰期，并且在临床试验中降低了成瘾性。在本研究中，我们将NKTR - 181与羟考酮进行比较，研究其信号传导和行为特征，以确定该化合物是否值得进一步进行治疗开发。对于这项临床前研究，我们使用了多种……和……检测方法。NKTR - 181的信号特征通过对啮齿动物背根神经节伤害性神经元中MOPr - Ca通道抑制的电生理评估来确定。基于异源细胞的检测方法用于评估偏向激动作用和受体转运。使用不同的啮齿动物行为模型来确定NKTR - 181诱导的有效和反射性伤害感受缓解以及药物寻求行为，这通过NKTR - 181的静脉自我给药（IVSA）来评估。我们发现，在G蛋白信号传导和Ca通道抑制检测中，NKTR - 181和羟考酮都是部分激动剂，并促进有限的MOPr脱敏。然而，NKTR - 181抑制Ca通道的机制与羟考酮不同，并诱导出不同的阻遏蛋白募集模式。此外，与羟考酮相比，NKTR - 181的受体结合速率较慢，Ca通道偶联速率也较慢。这种信号特征与羟考酮相比，抗伤害感受起效较慢且药物寻求行为有限相关。连同其已知的长半衰期和缓慢的血脑屏障转运，这些数据表明NKTR - 181可作为OUD的药物治疗方式进一步研究。
