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

Shu Yu Lin, Yu Hsien Kuo, Ya Wen Tien, Yi Yu Ke, Wan Ting Chang, Hsiao Fu Chang, Li Chin Ou, Ping Yee Law, Jing Hua Xi, Pao Luh Tao, Horace H. Loh, Yu Sheng Chao, Chuan Shih, Chiung Tong Chen, Shiu Hwa Yeh, Shau Hua Ueng

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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 ED50 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.

Original languageEnglish (US)
Pages (from-to)312-323
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume167
DOIs
StatePublished - Apr 1 2019

Bibliographical note

Funding Information:
This work was supported by grants 100-2325-B-400-006 , 101-2325-B-400-005 , 102-2325-B-400-005 , 103-2325-B-400-018 , 104-2325-B-400-008 , 105-2325-B-400-007 , 107-2320-B-400-007 and 107-2635-B-400-001 from the Ministry of Science and Technology , and Intramural Research Program of the National Health Research Institutes ( 04A1-BPPP03-005 , BP-103-PP-05 ), Taiwan. Appendix A

Publisher Copyright:
© 2019 Elsevier Masson SAS

Keywords

  • Antagonist
  • Antinociception
  • High-throughput screen
  • Naloxone
  • Naltrexone
  • Opioid receptor activation

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