Discovery of Biased Mu-Opioid Receptor Agonists for the Treatment of Pain
| Autor: | Ren Fengxia, Cheng Jingchao, Yu Zixing, Tong Kun, Zhong Bohua, Wei-Guo Shi, Ma Mengjun, Li Xiang |
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| Rok vydání: | 2019 |
| Předmět: |
Male
G protein Analgesic Drug Evaluation Preclinical Receptors Opioid mu Pain Pharmacology 01 natural sciences Biochemistry Mice Structure-Activity Relationship In vivo Drug Discovery polycyclic compounds Potency Animals General Pharmacology Toxicology and Pharmaceutics Receptor Analgesics Mice Inbred ICR Behavior Animal 010405 organic chemistry Chemistry Organic Chemistry Mu-Opioid Receptor Agonists beta-Arrestin 2 In vitro 0104 chemical sciences 010404 medicinal & biomolecular chemistry Disease Models Animal Molecular Medicine Signal Transduction |
| Zdroj: | ChemMedChem. 15(1) |
| ISSN: | 1860-7187 |
| Popis: | G protein-biased mu-opioid receptor (MOR) agonists have been developed as promising new potent analgesic drugs with fewer adverse side effects than standard MOR agonists. PZM21 represents a unique chemotype unrelated to known opioids, which makes it a desirable lead for modification to find analgesics with new chemical entities. In the present study, we synthesized and tested novel PZM21 derivatives as potent biased MOR agonists by introducing a benzodioxolane group to replace the hydroxybenzene of PZM21. The new compounds displayed more potent analgesic activities in vivo and greater bias toward G protein signaling in vitro than did PZM21. These results suggest that the benzodioxolane group is essential for the maintenance of bias. Compounds 7 i ((S)-1-(3-(benzo[d][1,3]dioxol-4-yl)-2-(dimethylamino)propyl)-3-phenethylurea) and 7 j ((S)-1-(3-(benzo[d][1,3]dioxol-4-yl)-2-(dimethylamino)propyl)-3-benzylurea) could serve as new leads for further modifications to find novel biased MOR agonists with greater G protein signaling potency and less β-arrestin-2 recruitment. |
| Databáze: | OpenAIRE |
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