Pain Medicine  |   May 2017
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
Author Notes
  • 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.).
  • P.-K.C. and S.-H.U. contributed equally to this article.
    P.-K.C. and S.-H.U. contributed equally to this article.×
  • Submitted for publication April 8, 2016. Accepted for publication January 17, 2017.
    Submitted for publication April 8, 2016. Accepted for publication January 17, 2017.×
  • Address correspondence to Dr. Yeh: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli 35053, Taiwan. bau9763@nhri.org.tw. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Pain Medicine / Basic Science / Pain Medicine / Pharmacology
Pain Medicine   |   May 2017
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
Anesthesiology 5 2017, Vol.126, 952-966. doi:10.1097/ALN.0000000000001568
Anesthesiology 5 2017, Vol.126, 952-966. doi:10.1097/ALN.0000000000001568
Abstract

Background: 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.

Methods: 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).

Results: 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.

Conclusions: Compound 1 produced antinociception with less gastrointestinal dysfunction than morphine.