期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 59, 期 24, 页码 11027-11038出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b01235
关键词
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资金
- AFPE Predoctoral Fellowship in Pharmaceutical Sciences
- Neurological Foundation
- Health Research Council of New Zealand
- Victoria University of Wellington
- NIH Shared Instrumentation grant [S10RR024664]
- NSF Major Research Instrumentation grant [0320648]
- National Science Foundation [ACI-1053575]
- [DA018151]
- [GM111385]
- [DA03049]
- [MH107053]
- [DA026434]
- [GM008545]
Opioids are widely used to treat millions suffering from pain, but their analgesic utility is limited due to associated side effects. Herein we report the development and evaluation of a chemical probe exhibiting analgesia and reduced opioid-induced side effects. This compound, kurkinorin (5), is a potent and selective p-opioid receptor (MOR) agonist (EC50 = 1.2 nM, >8000 mu/kappa selectivity). 5 is a biased activator of MOR-induced G-protein signaling over beta-arrestin-2 recruitment. Metadynamics simulations Of 5's binding to a MOR crystal structure suggest energetically preferred binding modes that differ from crystallographic ligands. In vivo studies with 5 demonstrate centrally mediated antinociception, significantly reduced rewarding effects, tolerance, and sedation. We propose that this novel MOR agonist may represent a valuable tool in distinguishing the pathways involved in MOR-induced analgesia from its side effects.
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