Discovery, structure-activity relationship studies, and anti-nociceptive effects of N-(1,2,3,4-tetrahydro-1-isoquinolinylmethyl)benzamides as novel opioid receptor agonists

Sheng Ren Chen, Yi Yu Ke, Teng Kuang Yeh, Shu Yu Lin, Li Chin Ou, Shu Chun Chen, Wan Ting Chang, Hsiao Fu Chang, Zih Huei Wu, Chih Chien Hsieh, Ping Yee Law, Horace H. Loh, Chuan Shih, Yiu Kay Lai, Shiu Hwa Yeh, Shau Hua Ueng

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

μ-Opioid receptor (MOR) agonists are analgesics used clinically for the treatment of moderate to severe pain, but their use is associated with severe adverse effects such as respiratory depression, constipation, tolerance, dependence, and rewarding effects. In this study, we identified N-({2-[(4-bromo-2-trifluoromethoxyphenyl)sulfonyl]-1,2,3,4-tetrahydro-1-isoquinolinyl}methyl)cyclohexanecarboxamide (1) as a novel opioid receptor agonist by high-throughput screening. Structural modifications made to 1 to improve potency and blood-brain-barrier (BBB) penetration resulted in compounds 45 and 46. Compound 45 was a potent MOR/KOR (κ-opioid receptor) agonist, and compound 46 was a potent MOR and medium KOR agonist. Both 45 and 46 demonstrated a significant anti-nociceptive effect in a tail-flick test performed in wild type (WT) B6 mice. The ED50value of 46 was 1.059 mg/kg, and the brain concentrations of 45 and 46 were 7424 and 11696 ng/g, respectively. Accordingly, compounds 45 and 46 are proposed for lead optimization and in vivo disease-related pain studies.

Original languageEnglish (US)
Pages (from-to)202-217
Number of pages16
JournalEuropean Journal of Medicinal Chemistry
Volume126
DOIs
StatePublished - 2017

Bibliographical note

Funding Information:
We are grateful to the grants 103-2325-B-400-018 and 104-2325-B-400-008 obtained from the Ministry of Science and Technology , and Intramural Research Program of National Health Research Institutes , Taiwan.

Publisher Copyright:
© 2016 Elsevier Masson SAS

Keywords

  • Anti-nociceptive effects
  • Blood-brain barrier
  • Penetration
  • Structure-activity relationship
  • Tail-flick test
  • κ-opioid receptor agonist
  • μ-opioid receptor agonist

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