國家衛生研究院 NHRI:Item 3990099045/11745
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    题名: The in vivo antinociceptive and mu-opioid receptor activating effects of the combination of N-phenyl-2′,4′-dimethyl-4,5′-bi-1,3-thiazol-2-amines and naloxone
    其它题名: The in vivo antinociceptive and μ-opioid receptor activating effects of the combination of N-phenyl-2′,4′-dimethyl-4,5′-bi-1,3-thiazol-2-amines and naloxone
    作者: Lin, SY;Kuo, YH;Tien, YW;Ke, YY;Chang, WT;Chang, HF;Ou, LC;Law, PY;Xi, JH;Tao, PL;Loh, HH;Chao, YS;Shih, C;Chen, CT;Yeh, SH;Ueng, SH
    贡献者: Institute of Biotechnology and Pharmaceutical Research;Center for Neuropsychiatric Research
    摘要: Morphine is widely used for the treatment of severe pain. This analgesic effect is mediated principally by the activation of μ-opioid receptors (MOR). However, prolonged activation of MOR also results in tolerance, dependence, addiction, constipation, nausea, sedation, and respiratory depression. To address this problem, we sought alternative ways to activate MOR – either by use of novel ligands, or via a novel activation mechanism. To this end, a series of compounds were screened using a sensitive CHO-K1/MOR/Gα15 cell-based FLIPR ® calcium high-throughput screening (HTS) assay, and the bithiazole compound 5a was identified as being able activate MOR in combination with naloxone. Structural modifications of 5a resulted in the discovery of lead compound 5j, which could effectively activate MOR in combination with the MOR antagonist naloxone or naltrexone. In vivo, naloxone in combination with 100 mg/kg of compound 5j elicited antinociception in a mouse tail-flick model with an ED 50 of 17.5 ± 4 mg/kg. These results strongly suggest that the mechanism by which the 5j/naloxone combination activates MOR is worthy of further study, as its discovery has the potential to yield an entirely novel class of analgesics.
    日期: 2019-04-01
    關聯: European Journal of Medicinal Chemistry. 2019 Apr 1;167:312-323.
    Link to: http://dx.doi.org/10.1016/j.ejmech.2019.01.063
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0223-5234&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000461728400021
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85061576132
    显示于类别:[翁紹華] 期刊論文
    [葉修華] 期刊論文
    [陳炯東] 期刊論文
    [石全(2014-2017)] 期刊論文
    [趙宇生(2002-2013)] 期刊論文
    [陶寶綠] 期刊論文
    [林書玉] 期刊論文

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