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DOI | 10.1126/science.aai8636 |
A nontoxic pain killer designed by modeling of pathological receptor conformations | |
Spahn, V.1; Del Vecchio, G.1; Labuz, D.1; Rodriguez-Gaztelumendi, A.1; Massaly, N.1,3; Temp, J.1; Durmaz, V.2; Sabri, P.2; Reidelbach, M.2; Machelska, H.1; Weber, M.2; Stein, C.1 | |
2017-03-03 | |
发表期刊 | SCIENCE |
ISSN | 0036-8075 |
EISSN | 1095-9203 |
出版年 | 2017 |
卷号 | 355期号:6328页码:966-+ |
文章类型 | Article |
语种 | 英语 |
国家 | Germany; USA |
英文摘要 | Indiscriminate activation of opioid receptors provides pain relief but also severe central and intestinal side effects. We hypothesized that exploiting pathological ( rather than physiological) conformation dynamics of opioid receptor-ligand interactions might yield ligands without adverse actions. By computer simulations at low pH, a hallmark of injured tissue, we designed an agonist that, because of its low acid dissociation constant, selectively activates peripheral mu-opioid receptors at the source of pain generation. Unlike the conventional opioid fentanyl, this agonist showed pH-sensitive binding, heterotrimeric guanine nucleotide-binding protein (G protein) subunit dissociation by fluorescence resonance energy transfer, and adenosine 3',5'-monophosphate inhibition in vitro. It produced injury-restricted analgesia in rats with different types of inflammatory pain without exhibiting respiratory depression, sedation, constipation, or addiction potential. |
领域 | 地球科学 ; 气候变化 ; 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000395181700043 |
WOS关键词 | MU-OPIOID RECEPTOR ; MORPHINE ; FENTANYL ; INSIGHTS |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/195545 |
专题 | 地球科学 资源环境科学 气候变化 |
作者单位 | 1.Charite, Free Univ Berlin, Dept Anesthesiol & Crit Care Med, Campus Benjamin Franklin,Hindenburgdamm 30, D-12203 Berlin, Germany; 2.Zuse Inst Berlin, Computat Mol Design, Takustr 7, D-14195 Berlin, Germany; 3.Washington Univ, Sch Med, Pain Ctr, Dept Anesthesiol, St Louis, MO 63110 USA |
推荐引用方式 GB/T 7714 | Spahn, V.,Del Vecchio, G.,Labuz, D.,et al. A nontoxic pain killer designed by modeling of pathological receptor conformations[J]. SCIENCE,2017,355(6328):966-+. |
APA | Spahn, V..,Del Vecchio, G..,Labuz, D..,Rodriguez-Gaztelumendi, A..,Massaly, N..,...&Stein, C..(2017).A nontoxic pain killer designed by modeling of pathological receptor conformations.SCIENCE,355(6328),966-+. |
MLA | Spahn, V.,et al."A nontoxic pain killer designed by modeling of pathological receptor conformations".SCIENCE 355.6328(2017):966-+. |
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