title: 1-(2,4-Dibromophenyl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one: A Novel Opioid Receptor Agonist with Less Accompanying Gastrointestinal Dysfunction than Morphine.
abstract: The authors investigated the pharmacology and signaling pathways of the opioid receptors modulated by compound 1, 1-(2,4-dibromophenyl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one.
  
  
  
  In vitro studies of compound 1 were assessed by using a radioligand-binding assay (n = 3), a cyclic adenosine monophosphate assay (n = 3), a β-arrestin assay (n = 3), an internalization assay (n = 3), and an immunohistochemistry (n = 8). In vivo studies of compound 1 were characterized using a tail-flick test (n = 5 to 6), tail-clip test (n = 7), von Frey hair test (n = 5), and charcoal meal test (n = 5).
  
  
  
  Compound 1 elicited robust effects in μ-opioid (mean ± SD; binding affinity: 15 ± 2 nM; cyclic adenosine monophosphate assay: 24 ± 6 nM), δ-opioid (82 ± 7 nM; 1.9 ± 0.1 μM), and κ-opioid (76 ± 9 nM; 1.4 ± 0.5 μM) receptor-expressing cells. Compound 1 acts as a full agonist of β-arrestin-2 recruitment in μ-opioid (1.1 ± 0.3 μM) and δ-opioid (9.7 ± 1.9 μM) receptor-expressing cells. Compound 1 caused less gastrointestinal dysfunction (charcoal meal test: morphine: 82 ± 5%; compound 1: 42 ± 5%) as well as better antinociception in mechanical pain hypersensitivity (tail-clip test: morphine: 10 ± 3 s; compound 1: 19 ± 1 s) and in cancer-induced pain (von Frey hair test: morphine: 0.1 ± 0.1 g; compound 1: 0.3 ± 0.1 g) than morphine at equi-antinociceptive doses.
  
  
  
  Compound 1 produced antinociception with less gastrointestinal dysfunction than morphine.
authors.affiliation: From the Institute of Biotechnology and Pharmaceutical Research (P.-K.C., S.-H.U., L.-C.O., T.-K.Y., W.-T.C., H.-F.C., S.-C.C., M.-F.C., C.-T.C., C.S., S.-H.Y.) and Center for Neuropsychiatric Research (P.-L.T.), National Health Research Institutes, Zhunan, Taiwan; Department of Pharmacology, Medical School University of Minnesota, Minneapolis, Minnesota (P.-Y.L., H.H.L.); and the Ph.D. Program for Neural Regenerative Medicine, Taipei Medical University, Taipei, Taiwan (J.-Y.C., S.-H.Y.).
authors.forename: Po-Kuan
authors.initials: PK
authors.lastname: Chao
authors.forename: Shau-Hua
authors.initials: SH
authors.lastname: Ueng
authors.forename: Li-Chin
authors.initials: LC
authors.lastname: Ou
authors.forename: Teng-Kuang
authors.initials: TK
authors.lastname: Yeh
authors.forename: Wan-Ting
authors.initials: WT
authors.lastname: Chang
authors.forename: Hsiao-Fu
authors.initials: HF
authors.lastname: Chang
authors.forename: Shu-Chun
authors.initials: SC
authors.lastname: Chen
authors.forename: Pao-Luh
authors.initials: PL
authors.lastname: Tao
authors.forename: Ping-Yee
authors.initials: PY
authors.lastname: Law
authors.forename: Horace H
authors.initials: HH
authors.lastname: Loh
authors.forename: Ming-Fu
authors.initials: MF
authors.lastname: Cheng
authors.forename: Jian-Ying
authors.initials: JY
authors.lastname: Chuang
authors.forename: Chiung-Tong
authors.initials: CT
authors.lastname: Chen
authors.forename: Chuan
authors.initials: C
authors.lastname: Shih
authors.forename: Shiu-Hwa
authors.initials: SH
authors.lastname: Yeh
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000503:physiopathology; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine; D011957:Receptors, Opioid / Q000819:agonists*
chemical_list: C000596442:1-(2,4-dibromophenyl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one; D000701:Analgesics, Opioid; D007191:Indazoles; D011957:Receptors, Opioid; D009020:Morphine