1-(2,4-Dibromophenyl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-4 H -indazol-4-one: A Novel Opioid Receptor Agonist with Less Accompanying Gastrointestinal Dysfunction than Morphine

Po Kuan Chao, Shau Hua Ueng, Li Chin Ou, Teng Kuang Yeh, Wan Ting Chang, Hsiao Fu Chang, Shu Chun Chen, Pao Luh Tao, Ping Yee Law, Horace H. Loh, Ming Fu Cheng, Jian Ying Chuang, Chiung Tong Chen, Chuan Shih, Shiu Hwa Yeh

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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.

Original languageEnglish
Pages (from-to)952-966
Number of pages15
JournalAnesthesiology
Volume126
Issue number5
DOIs
Publication statusPublished - May 1 2017

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ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Chao, P. K., Ueng, S. H., Ou, L. C., Yeh, T. K., Chang, W. T., Chang, H. F., Chen, S. C., Tao, P. L., Law, P. Y., Loh, H. H., Cheng, M. F., Chuang, J. Y., Chen, C. T., Shih, C., & Yeh, S. H. (2017). 1-(2,4-Dibromophenyl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-4 H -indazol-4-one: A Novel Opioid Receptor Agonist with Less Accompanying Gastrointestinal Dysfunction than Morphine. Anesthesiology, 126(5), 952-966. https://doi.org/10.1097/ALN.0000000000001568