國家衛生研究院 NHRI:Item 3990099045/11745

NHRI > Institute of Biotechnology and Pharmaceutical Research > Shau-Hua Ueng > Periodical Articles > Item 3990099045/11745

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Title:	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
Other Titles:	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
Authors:	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
Contributors:	Institute of Biotechnology and Pharmaceutical Research;Center for Neuropsychiatric Research
Abstract:	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.
Date:	2019-04-01
Relation:	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
Appears in Collections:	[Shau-Hua Ueng] Periodical Articles [Shiu-Hwa Yeh] Periodical Articles [Chiung-Tong Chen] Periodical Articles [Chuan Shih(2014-2017)] Periodical Articles [Yu-Sheng Chao(2002-2013)] Periodical Articles [Pao-Luh Tao] Periodical Articles [Shu-Yu Lin] Periodical Articles

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