Discovery, structure-activity relationship studies, and anti-nociceptive effects of 1-phenyl-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one as novel opioid receptor agonists

Ming Fu Cheng, Li Chin Ou, Shu Chun Chen, Wan Ting Chang, Ping-Yee Law, Horace H Loh, Yu Sheng Chao, Chuan Shih, Shiu Hwa Yeh, Shau Hua Ueng

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

The μ-opioid receptor (MOR) is the major opioid receptor targeted by most analgesics in clinical use. However, the use of all known MOR agonists is associated with severe adverse effects. We reported that the 1-phenyl-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-ones are novel opioid receptor agonists. Subsequent structural modification resulted in the potent MOR/KOR (κ-opioid receptor) agonists 19, 20, and 21. Testing the analgesic effect of these in WT B6 mice (tail-flick test) gave ED50 values of 8.4, 10.9, and 26.6 mg/kg, respectively. The 1-phenyl-3,6,6-trimethyl-1,5,6,7- tetrahydro-4H-indazol-4-one core could be addressed in 1 or 2 synthetic steps with moderate to high percent of yield. In the adenylyl cyclase assay, compound 19 displayed a MOR/KOR agonist profile, with IC50 values of 0.73 and 0.41 μM, respectively. Current results suggest that compound 19 is a promising lead to go further development and in vitro/in vivo adverse effects studies.

Original languageEnglish (US)
Pages (from-to)4694-4703
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number17
DOIs
StatePublished - Sep 1 2014

Bibliographical note

Funding Information:
We are grateful to National Health Research Institutes and National Science Council of the Republic of China (100NP1004) for financial support.

Keywords

  • Anti-nociceptive effects
  • Structure-activity relationship
  • Tail-flick test
  • μ/κ opioid receptor agonist

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