title: 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.
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 26.6mg/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 0.41μM, respectively. Current results suggest that compound 19 is a promising lead to go further development and in vitro/in vivo adverse effects studies.
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC.
authors.forename: Ming-Fu
authors.initials: MF
authors.lastname: Cheng
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC.
authors.forename: Li-Chin
authors.initials: LC
authors.lastname: Ou
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC.
authors.forename: Shu-Chun
authors.initials: SC
authors.lastname: Chen
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC.
authors.forename: Wan-Ting
authors.initials: WT
authors.lastname: Chang
authors.affiliation: Department of Pharmacology, University of Minnesota, Medical School, Minneapolis, MN 55455, USA.
authors.forename: Ping-Yee
authors.initials: PY
authors.lastname: Law
authors.affiliation: Department of Pharmacology, University of Minnesota, Medical School, Minneapolis, MN 55455, USA.
authors.forename: Horace H
authors.initials: HH
authors.lastname: Loh
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC.
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC.
authors.forename: Chuan
authors.initials: C
authors.lastname: Shih
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC. Electronic address: bau9763@bp.nhri.org.tw.
authors.forename: Shiu-Hwa
authors.initials: SH
authors.lastname: Yeh
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC. Electronic address: shueng@nhri.org.tw.
authors.forename: Shau-Hua
authors.initials: SH
authors.lastname: Ueng
mesh_terms: D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D020297:Mice, Congenic; D015394:Molecular Structure; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013329:Structure-Activity Relationship; D013623:Tail / Q000187:drug effects
chemical_list: C000596442:1-(2,4-dibromophenyl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one; D000700:Analgesics; D007191:Indazoles; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu
keywords: Anti-nociceptive effects; Structure–activity relationship; Tail-flick test; μ/κ opioid receptor agonist