Activation of μ receptors by SR-17018 through a distinctive mechanism

IF 4.6 2区 医学 Q1 NEUROSCIENCES
Samuel Singleton , Clara Dieterle , David J. Walker , Tyko Runeberg , Andrew S. Oswald , Greta Rosenqvist , Laura Robertson , Taylor McCarthy , Shuvam Sarkar , Daniel Baptista-Hon , Tim G. Hales
{"title":"Activation of μ receptors by SR-17018 through a distinctive mechanism","authors":"Samuel Singleton ,&nbsp;Clara Dieterle ,&nbsp;David J. Walker ,&nbsp;Tyko Runeberg ,&nbsp;Andrew S. Oswald ,&nbsp;Greta Rosenqvist ,&nbsp;Laura Robertson ,&nbsp;Taylor McCarthy ,&nbsp;Shuvam Sarkar ,&nbsp;Daniel Baptista-Hon ,&nbsp;Tim G. Hales","doi":"10.1016/j.neuropharm.2024.110093","DOIUrl":null,"url":null,"abstract":"<div><p>Agonists at μ opioid receptors relieve acute pain, however, their long-term use is limited by side effects, which may involve β-arrestin2. Agonists biased against β-arrestin2 recruitment may be advantageous. However, the classification of bias may be compromised by assays utilising overexpressed μ receptors which overestimate efficacy for G-protein activation. There is a need for re-evaluation with restricted receptor availability to determine accurate agonist efficacies. We depleted μ receptor availability in PathHunter CHO cells using the irreversible antagonist, β-funaltrexamine (β-FNA), and compared efficacies and apparent potencies of twelve agonists, including several previously reported as biased, in β-arrestin2 recruitment and cAMP assays. With full receptor availability all agonists had partial efficacy for stimulating β-arrestin2 recruitment relative to DAMGO, while only TRV130 and buprenorphine were partial agonists as inhibitors of cAMP accumulation. Limiting receptor availability by prior exposure to β-FNA (100 nM) revealed morphine, oxycodone, PZM21, herkinorin, U47700, tianeptine and U47931e are also partial agonists in the cAMP assay. The efficacies of all agonists, except SR-17018, correlated between β-arrestin2 recruitment and cAMP assays, with depleted receptor availability in the latter. Furthermore, naloxone and cyprodime exhibited non-competitive antagonism of SR-17018 in the β-arrestin2 recruitment assay. Limited antagonism by naloxone was also non-competitive in the cAMP assay, while cyprodime was competitive. Furthermore, SR-17018 only negligibly diminished β-arrestin2 recruitment stimulated by DAMGO (1 μM), whereas fentanyl, morphine and TRV130 all exhibited the anticipated competitive inhibition. The data suggest that SR-17018 achieves bias against β-arrestin2 recruitment through interactions with μ receptors outside the orthosteric agonist site.</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"258 ","pages":"Article 110093"},"PeriodicalIF":4.6000,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuropharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0028390824002624","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0

Abstract

Agonists at μ opioid receptors relieve acute pain, however, their long-term use is limited by side effects, which may involve β-arrestin2. Agonists biased against β-arrestin2 recruitment may be advantageous. However, the classification of bias may be compromised by assays utilising overexpressed μ receptors which overestimate efficacy for G-protein activation. There is a need for re-evaluation with restricted receptor availability to determine accurate agonist efficacies. We depleted μ receptor availability in PathHunter CHO cells using the irreversible antagonist, β-funaltrexamine (β-FNA), and compared efficacies and apparent potencies of twelve agonists, including several previously reported as biased, in β-arrestin2 recruitment and cAMP assays. With full receptor availability all agonists had partial efficacy for stimulating β-arrestin2 recruitment relative to DAMGO, while only TRV130 and buprenorphine were partial agonists as inhibitors of cAMP accumulation. Limiting receptor availability by prior exposure to β-FNA (100 nM) revealed morphine, oxycodone, PZM21, herkinorin, U47700, tianeptine and U47931e are also partial agonists in the cAMP assay. The efficacies of all agonists, except SR-17018, correlated between β-arrestin2 recruitment and cAMP assays, with depleted receptor availability in the latter. Furthermore, naloxone and cyprodime exhibited non-competitive antagonism of SR-17018 in the β-arrestin2 recruitment assay. Limited antagonism by naloxone was also non-competitive in the cAMP assay, while cyprodime was competitive. Furthermore, SR-17018 only negligibly diminished β-arrestin2 recruitment stimulated by DAMGO (1 μM), whereas fentanyl, morphine and TRV130 all exhibited the anticipated competitive inhibition. The data suggest that SR-17018 achieves bias against β-arrestin2 recruitment through interactions with μ receptors outside the orthosteric agonist site.

SR-17018 通过独特的机制激活μ受体。
μ阿片受体激动剂可缓解急性疼痛,但其长期使用受到副作用的限制,副作用可能涉及β-阿司匹林2。偏向β-阿司匹林2募集的激动剂可能具有优势。然而,利用过表达的 μ 受体进行的检测可能会影响对偏倚的分类,因为过表达的 μ 受体会高估激活 G 蛋白的功效。有必要在受体可用性受到限制的情况下进行重新评估,以确定准确的激动剂功效。我们在 PathHunter CHO 细胞中使用不可逆的拮抗剂β-funaltrexamine(β-FNA)耗尽了μ受体的可用性,并比较了十二种激动剂在β-arrestin2 招募和 cAMP 试验中的功效和表观效力,其中包括之前报道的几种有偏差的激动剂。与 DAMGO 相比,在受体完全可用的情况下,所有激动剂在刺激 β-arrestin2 募集方面都有部分功效,而只有 TRV130 和丁丙诺啡是抑制 cAMP 积累的部分激动剂。通过事先暴露于 β-FNA(100 nM)来限制受体的可用性,发现吗啡、羟考酮、PZM21、herkinorin、U47700、tianeptine 和 U47931e 也是 cAMP 试验中的部分激动剂。除 SR-17018 外,所有激动剂的功效都与β-arrestin2 招募和 cAMP 试验相关,后者的受体可用性被耗尽。此外,纳洛酮和环丙哌啶在 β-阿restin2募集试验中表现出对 SR-17018 的非竞争性拮抗。在 cAMP 试验中,纳洛酮的有限拮抗作用也是非竞争性的,而环丙肟则是竞争性的。此外,SR-17018 对 DAMGO(1 μM)刺激的 β-arrestin2 募集的减弱作用可以忽略不计,而芬太尼、吗啡和 TRV130 都表现出预期的竞争性抑制作用。这些数据表明,SR-17018 通过与正交激动剂位点外的μ受体相互作用,实现了对β-arrestin2 募集的偏向性抑制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Neuropharmacology
Neuropharmacology 医学-神经科学
CiteScore
10.00
自引率
4.30%
发文量
288
审稿时长
45 days
期刊介绍: Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信