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

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

Research output: Contribution to journalArticle

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 (US)
JournalAnesthesiology
DOIs
StateAccepted/In press - Feb 17 2017

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Opioid Receptors
Morphine
Opioid Analgesics
Arrestin
Charcoal
Surgical Instruments
Cyclic AMP
Meals
Pain
Radioligand Assay
Immunohistochemistry
Pharmacology
Neoplasms
In Vitro Techniques

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

MeSH PubMed subject areas

  • Journal Article

Cite this

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

In: Anesthesiology, 17.02.2017.

Research output: Contribution to journalArticle

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

In: Anesthesiology, 17.02.2017.

Research output: Contribution to journalArticle

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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 = "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.",
author = "Chao, {Po Kuan} and Ueng, {Shau Hua} and Ou, {Li Chin} and Yeh, {Teng Kuang} and Chang, {Wan Ting} and Chang, {Hsiao Fu} and Chen, {Shu Chun} and Tao, {Pao Luh} and Law, {Ping Yee} and Loh, {Horace H.} and Cheng, {Ming Fu} and Chuang, {Jian Ying} and Chen, {Chiung Tong} and Chuan Shih and Yeh, {Shiu Hwa}",
year = "2017",
month = "2",
doi = "10.1097/ALN.0000000000001568",
journal = "Anesthesiology",
issn = "0003-3022",
publisher = "Lippincott Williams and Wilkins",

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TY - JOUR

T1 - 1-(2,4-Dibromophenyl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one

T2 - Anesthesiology

AU - Chao,Po Kuan

AU - Ueng,Shau Hua

AU - Ou,Li Chin

AU - Yeh,Teng Kuang

AU - Chang,Wan Ting

AU - Chang,Hsiao Fu

AU - Chen,Shu Chun

AU - Tao,Pao Luh

AU - Law,Ping Yee

AU - Loh,Horace H.

AU - Cheng,Ming Fu

AU - Chuang,Jian Ying

AU - Chen,Chiung Tong

AU - Shih,Chuan

AU - Yeh,Shiu Hwa

PY - 2017/2/17

Y1 - 2017/2/17

N2 - 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.

AB - 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.

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DO - 10.1097/ALN.0000000000001568

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