Discovery, structure-activity relationship studies, and anti-nociceptive effects of N-(1,2,3,4-tetrahydro-1-isoquinolinylmethyl)benzamides as novel opioid receptor agonists

被引:13
作者
Chen, Sheng-Ren [1 ]
Ke, Yi-Yu [1 ]
Yeh, Teng-Kuang [1 ]
Lin, Shu-Yu [1 ]
Ou, Li-Chin [1 ]
Chen, Shu-Chun [1 ]
Chang, Wan-Ting [1 ]
Chang, Hsiao-Fu [1 ]
Wu, Zih-Huei [1 ]
Hsieh, Chih-Chien [1 ]
Law, Ping-Yee [2 ]
Loh, Horace H. [2 ]
Shih, Chuan [1 ]
Lai, Yiu-Kay [3 ,4 ]
Yeh, Shiu-Hwa [1 ,5 ]
Ueng, Shau-Hua [1 ]
机构
[1] Natl Hlth Res Inst, Inst Biotechnol & Pharmaceut Res, Jhunan 35053, Miaoli County, Taiwan
[2] Univ Minnesota, Sch Med, Dept Pharmacol, Minneapolis, MN 55455 USA
[3] Natl Tsing Hua Univ, Inst Biotechnol, Hsinchu, Taiwan
[4] Natl Tsing Hua Univ, Dept Life Sci, Hsinchu, Taiwan
[5] Taipei Med Univ, PhD Program Neural Regenerat Med, Taipei 110, Taiwan
关键词
mu-opioid receptor agonist; kappa-opioid receptor agonist; Structure-activity relationship; Blood-brain barrier; Penetration; Anti-nociceptive effects; Tail-flick test; BIOLOGICAL EVALUATION; RHESUS-MONKEYS; MU; COCAINE; EXPRESSION; MORPHINE; LIGANDS; CLONING; DESIGN; BRAIN;
D O I
10.1016/j.ejmech.2016.09.003
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
mu-Opioid receptor (MOR) agonists are analgesics used clinically for the treatment of moderate to severe pain, but their use is associated with severe adverse effects such as respiratory depression, constipation, tolerance, dependence, and rewarding effects. In this study, we identified N-((2-[(4-bromo-2trifluoromethoxyphenyl)sulfony1]-1,2,3,4-tetrahydro-1-isoquinolinyl}methyl)cyclohexanecarboxamide (1) as a novel opioid receptor agonist by high-throughput screening. Structural modifications made to 1 to improve potency and blood-brain-barrier (BBB) penetration resulted in compounds 45 and 46. Compound 45 was a potent MOR/KOR (kappa-opioid receptor) agonist, and compound 46 was a potent MOR and medium KOR agonist. Both 45 and 46 demonstrated a significant anti-nociceptive effect in a tail-flick test performed in wild type (WT) B6 mice. The ED50 value of 46 was 1.059 mg/kg, and the brain concentrations of 45 and 46 were 7424 and 11696 ng/g, respectively. Accordingly, compounds 45 and 46 are proposed for lead optimization and in vivo disease-related pain studies. (C) 2016 Elsevier Masson SAS. All rights reserved.
引用
收藏
页码:202 / 217
页数:16
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