Wei Fu Group (School of Pharmacy, Fudan University) and Jinggen Liu Group (Shanghai Institute of Materia Medica, Chinese Academy of Sciences) has made progress in the study of novel selective μOR agonists as well as a structural basis for development of potential analgesic candidates. The discovery of a new MOR agonist (3R, 4S)-9d and its metabolite 10a is of significance for simplifying the chemical structure of classic opioids, expanding the structure of MOR agonists, and discovering new analgesic compounds. The relevant results were published in full text in the Journal of Medicinal Chemistry (the original link: https://doi.org/10.1021/acs.jmedchem.1c00722), an international authoritative journal in the field of medicinal chemistry.
MOR agonist 9d and its metabolite 10a and MOR mode of action
The classical Opioids, such as morphine and pethidine, are indispensable for clinical analgesia, but they have severe side effects such as respiratory depression and addiction, the mechanisms are related to the activation of opioid μ receptors (MOR). Improving the activity and safety of MOR agonists through small molecular structure innovation is one of the research directions of analgesic drugs. The U.S. Food and Drug Administration has also approved tapentadol (Tapentadol, 2008), Olceridine (TRV130, 2020) and other MOR agonists with novel chemical structures and distinctive pharmacological mechanisms for clinical analgesia for more than a decade. The structure of morphine was simplified based on the piperidine. After multiple rounds of design, synthesis, activity screening and evaluation, (3R, 4S)-9d and its metabolite 10a were found to be representative new MOR agonists with the N-phenylacetyl piperidine scaffold. (3R, 4S)-9d showed strong analgesic activity in both hot plate and writhing models. Through the subtle design of methoxy prodrugs on the benzene ring, the compound successfully passed through the blood-brain barrier. The brain is metabolized into demethylated metabolite 10a, which is the key factor for its potent analgesic activity. Molecular dynamics simulations have elucidated the signal transduction mechanism of 10a-mediated MOR receptors.
10a-mediated MOR receptor signal transduction mechanism
Huoming Huang, Ph.D. and Peng Xie Ph.D. and Xinwei Li, M.S. (School of Pharmacy, Fudan University) and Xueping Li, Ph.D. (Shanghai Institute of Materia Medica, Chinese Academy of Sciences) shared the co-first authorship of this manuscript; Prof. Dr. Wei Fu and Assoc. Prof. Dr. Wei Li (School of Pharmacy, Fudan University) and Assoc. Prof. Yujun Wang (Shanghai Institute of Materia Medica, Chinese Academy of Sciences) are the co-corresponding authors of this article. This work has been funded by the National Natural Science Foundation of China, the Shanghai Municipal Science and Technology Commission and the Youth Innovation Promotion Association of the Chinese Academy of Sciences.