Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Anesthesiology (Philadelphia), 2017-05, Vol.126 (5), p.952-966

Ort / Verlag

United States: Copyright by , the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 affinity15 ± 2 nM; cyclic adenosine monophosphate assay24 ± 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 testmorphine82 ± 5%; compound 142 ± 5%) as well as better antinociception in mechanical pain hypersensitivity (tail-clip testmorphine10 ± 3 s; compound 119 ± 1 s) and in cancer-induced pain (von Frey hair testmorphine0.1 ± 0.1 g; compound 10.3 ± 0.1 g) than morphine at equi-antinociceptive doses. CONCLUSIONS:Compound 1 produced antinociception with less gastrointestinal dysfunction than morphine.