Structure-based discovery of opioid analgesics with reduced side effects

被引：703

作者：

Manglik, Aashish ^{[1
]}

Lin, Henry ^{[2
]}

Aryal, Dipendra K. ^{[3
]}

McCorvy, John D. ^{[3
]}

Dengler, Daniela ^{[4
]}

Corder, Gregory ^{[5
]}

Levit, Anat ^{[2
]}

Kling, Ralf C. ^{[4
,6
]}

Bernat, Viachaslau ^{[4
]}

Huebner, Harald ^{[4
]}

Huang, Xi-Ping ^{[3
]}

Sassano, Maria F. ^{[3
]}

Giguere, Patrick M. ^{[3
]}

Loeber, Stefan ^{[4
]}

Duan, Da ^{[2
]}

Scherrer, Gregory ^{[1
,5
]}

Kobilka, Brian K. ^{[1
]}

Gmeiner, Peter ^{[4
]}

Roth, Bryan L. ^{[3
]}

Shoichet, Brian K. ^{[2
]}

机构：

[1] Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA

[2] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA

[3] UNC Chapel Hill Med Sch, Dept Pharmacol, Chapel Hill, NC 27514 USA

[4] Univ Erlangen Nurnberg, Dept Chem & Pharm, Schuhstr 19, D-91052 Erlangen, Germany

[5] Stanford Univ, Sch Med, Stanford Neurosci Inst, Dept Anesthesiol Perioperat & Pain Med,Neurosurg, Stanford, CA 94305 USA

[6] Paracelsus Med Univ, Inst Physiol & Pathophysiol, D-90419 Nurnberg, Germany

来源：

NATURE | 2016年 / 537卷 / 7619期

基金：

美国国家卫生研究院;

关键词：

A(2A) RECEPTOR ANTAGONISTS; PROTEIN-COUPLED RECEPTOR; CRYSTAL-STRUCTURE; MORPHINE ANALGESIA; LIGAND DISCOVERY; BIASED AGONISM; MICE; PAIN; IDENTIFICATION; MODEL;

D O I：

10.1038/nature19112

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Morphine is an alkaloid from the opium poppy used to treat pain. The potentially lethal side effects of morphine and related opioids-which include fatal respiratory depression-are thought to be mediated by mu-opioid-receptor (mu OR) signalling through the beta-arrestin pathway or by actions at other receptors. Conversely, G-protein mu OR signalling is thought to confer analgesia. Here we computationally dock over 3 million molecules against the mu OR structure and identify new scaffolds unrelated to known opioids. Structure-based optimization yields PZM21-a potent G(i) activator with exceptional selectivity for mu OR and minimal beta-arrestin-2 recruitment. Unlike morphine, PZM21 is more efficacious for the affective component of analgesia versus the reflexive component and is devoid of both respiratory depression and morphine-like reinforcing activity in mice at equi-analgesic doses. PZM21 thus serves as both a probe to disentangle mu OR signalling and a therapeutic lead that is devoid of many of the side effects of current opioids.

引用

页码：185 / +

页数：22

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