Slow dissociation kinetics of fentanyls and nitazenes correlates with reduced sensitivity to naloxone reversal at the μ-opioid receptor.

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Norah Alhosan, Damiana Cavallo, Marina Santiago, Eamonn Kelly, Graeme Henderson
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引用次数: 0

Abstract

Background and purpose: Fentanyls and nitazenes are μ-opioid receptor agonists responsible for a large number of opioid overdose deaths. Here, we determined the potency, dissociation kinetics and antagonism by naloxone at the μ receptor of several fentanyl and nitazene analogues, compared to morphine and DAMGO.

Experimental approach: In vitro assays of G protein activation and signalling and arrestin recruitment were performed. AtT20 cells expressing μ receptors were loaded with a membrane potential dye and changes in fluorescence used to determine agonist potency, dissociation kinetics and susceptibility to antagonism by naloxone. BRET experiments were undertaken in HEK293T cells expressing μ receptors to assess Gi protein activation and β-arrestin 2 recruitment.

Key results: The apparent rate of agonist dissociation from the μ receptor varied: morphine, DAMGO, alfentanil and fentanyl dissociated rapidly, whereas isotonitazene, etonitazene, ohmefentanyl and carfentanil dissociated slowly. Slowly dissociating agonists were more resistant to antagonism by naloxone. For carfentanil, the slow apparent rate of dissociation was not because of G protein receptor kinase-mediated arrestin recruitment as its apparent rate of dissociation was not increased by inhibition of G protein-coupled receptor kinases (GRKs) with Compound 101. The in vitro relative potencies of fentanyls and nitazenes compared to morphine were much lower than that previously observed in in vivo experiments.

Conclusions and implications: With fentanyls and nitazenes that slowly dissociate from the μ receptor, antagonism by naloxone is pseudo-competitive. In overdoses involving fentanyls and nitazenes, higher doses of naloxone may be required for reversal than those normally used to reverse heroin overdose.

芬太尼类和硝氮类药物的缓慢解离动力学与纳洛酮逆转μ-阿片受体的敏感性降低有关。
背景和目的:芬太尼类和硝氮类是μ-阿片受体激动剂,是造成大量阿片类药物过量致死的原因。在此,我们测定了几种芬太尼和硝氮类似物与吗啡和 DAMGO 相比在 μ 受体上的效力、解离动力学和纳洛酮拮抗作用:实验方法:对 G 蛋白活化和信号传导以及捕获素招募进行体外检测。表达 μ 受体的 AtT20 细胞装载了膜电位染料,荧光变化用于确定激动剂的效力、解离动力学和纳洛酮的拮抗敏感性。在表达μ受体的HEK293T细胞中进行了BRET实验,以评估Gi蛋白的激活和β-arrestin 2的招募:吗啡、DAMGO、阿芬太尼和芬太尼的解离速度很快,而异托尼达嗪、依托尼达嗪、奥美芬太尼和卡芬太尼的解离速度较慢。缓慢解离的激动剂对纳洛酮的拮抗作用更具抵抗力。对于卡芬太尼来说,表观解离速度慢并不是因为 G 蛋白受体激酶介导的停滞素招募,因为用化合物 101 抑制 G 蛋白偶联受体激酶(GRKs)并不会增加其表观解离速度。与吗啡相比,芬太尼类和硝氮类化合物的体外相对效力远低于之前在体内实验中观察到的效力:芬太尼类和硝氮类药物能缓慢地与μ受体解离,纳洛酮的拮抗作用是假竞争性的。在芬太尼类和硝氮类药物用药过量的情况下,可能需要比通常用于逆转海洛因用药过量的纳洛酮剂量更大的纳洛酮才能逆转。
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来源期刊
CiteScore
15.40
自引率
12.30%
发文量
270
审稿时长
2.0 months
期刊介绍: The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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