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Molecules 2019, 24(2), 259; https://doi.org/10.3390/molecules24020259

Synthesis and Evaluation of Novel Biased μ-Opioid-Receptor (μOR) Agonists

1
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China
2
National Glycoengineering Research Center and Shandong Provincial Key Laboratory of Carbohydrate Chemistry and Glycobiology, Shandong University, 27 Shanda Nan Lu, Jinan 250100, China
3
TaizhouHuayuan Med Tech Company LTD, 1 Yaocheng Avenue, Taizhou 225312, China
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Received: 13 December 2018 / Revised: 5 January 2019 / Accepted: 10 January 2019 / Published: 11 January 2019
(This article belongs to the Section Medicinal Chemistry)
Full-Text   |   PDF [1976 KB, uploaded 11 January 2019]   |  

Abstract

‘Biased’ ligands of G protein-coupled receptors (GPCRs) represent a type of promising analgesic with reduced on-target side effects. PZM21, a potent μ-opioid-receptor (μOR)-biased agonist with a new chemical scaffold compared to classic opioids, has been identified as a therapeutic lead molecule for treating pain. In the current study, novel PZM21 analogues were synthesized and evaluated for their in vitro and in vivo efficacy. Novel compound 7a and PZM21 demonstrated undetectable β-arrestin-2 recruitment, however, their analgesic effects need to be further confirmed. Compounds 7b, 7d, and 7g were stronger analgesics than PZM21 in both the mouse formalin injection assay and the writhing test. Compound 7d was the most potent analogue, requiring a dose that was 1/16th to 1/4th of that of PZM21 for its analgesic activity in the two assays, respectively. Therefore, compound 7d could serve as a lead to develop new biased μOR agonists for treating pain. View Full-Text
Keywords: μOR-biased agonist; PZM21; Gi signaling pathway; β-arrestin-2 recruitment; structure–activity relationship μOR-biased agonist; PZM21; Gi signaling pathway; β-arrestin-2 recruitment; structure–activity relationship
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Ma, M.; Sun, J.; Li, M.; Yu, Z.; Cheng, J.; Zhong, B.; Shi, W. Synthesis and Evaluation of Novel Biased μ-Opioid-Receptor (μOR) Agonists. Molecules 2019, 24, 259.

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