期刊
NATURE
卷 537, 期 7619, 页码 185-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature19112
关键词
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资金
- US National Institutes of Health [GM106990, DA036246, GM59957]
- National Institutes of Mental Health Psychoactive Drug Screening Program
- Michael Hooker Distinguished Professorship
- German Research Foundation [Gm 13/10, GRK 1910]
- Stanford University Medical Scientist Training Program [T32GM007365]
- American Heart Association [12PRE8120001]
- [DA017204]
- [DA035764]
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.
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