Malcolm Nicholas J, Palkovic Barbara, Sprague Daniel J, Calkins Maggie M, Lanham Janelle K, Halberstadt Adam L, Stucke Astrid G, McCorvy John D
Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
iScience. 2023 Jun 13;26(7):107121. doi: 10.1016/j.isci.2023.107121. eCollection 2023 Jul 21.
Synthetic opioids are increasingly challenging to combat the opioid epidemic and act primarily at opioid receptors, chiefly the G protein-coupled receptor (GPCR) μ-opioid receptor (MOR), which signals through G protein-dependent and β-arrestin pathways. Using a bioluminescence resonance energy transfer (BRET) system, we investigate GPCR-signaling profiles by synthetic nitazenes, which are known to cause overdose and death due to respiratory depression. We show that isotonitazene and its metabolite, -desethyl isotonitazene, are very potent MOR-selective superagonists, surpassing both DAMGO G protein and β-arrestin recruitment activity, which are properties distinct from other conventional opioids. Both isotonitazene and -desethyl isotonitazene show high potency in mouse analgesia tail-flick assays, but -desethyl isotonitazene shows longer-lasting respiratory depression compared to fentanyl. Overall, our results suggest that potent MOR-selective superagonists may be a pharmacological property predictive of prolonged respiratory depression resulting in fatal consequences and should be examined for future opioid analgesics.
合成阿片类药物在对抗阿片类药物流行方面面临越来越大的挑战，它们主要作用于阿片受体，主要是G蛋白偶联受体（GPCR）μ-阿片受体（MOR），该受体通过G蛋白依赖性和β-抑制蛋白途径发出信号。我们使用生物发光共振能量转移（BRET）系统，研究了合成硝氮烯的GPCR信号传导谱，已知硝氮烯会因呼吸抑制导致过量用药和死亡。我们发现异硝氮烯及其代谢物去乙基异硝氮烯是非常有效的MOR选择性超级激动剂，超过了DAMGO的G蛋白和β-抑制蛋白募集活性，这是与其他传统阿片类药物不同的特性。异硝氮烯和去乙基异硝氮烯在小鼠甩尾镇痛试验中均显示出高效力，但与芬太尼相比，去乙基异硝氮烯显示出更持久的呼吸抑制作用。总体而言，我们的结果表明，强效的MOR选择性超级激动剂可能是一种预测会导致致命后果的长期呼吸抑制的药理学特性，未来应针对阿片类镇痛药进行研究。
