title: Discovery, structure-activity relationship studies, and anti-nociceptive effects of N-(1,2,3,4-tetrahydro-1-isoquinolinylmethyl)benzamides as novel opioid receptor agonists.
abstract: μ-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-2-trifluoromethoxyphenyl)sulfonyl]-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 (κ-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 ED50value 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.
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, 35053, Taiwan; Institute of Biotechnology and Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan.
authors: Sheng-Ren
authors: SR
authors: Chen
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, 35053, Taiwan.
authors: Yi-Yu
authors: YY
authors: Ke
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, 35053, Taiwan.
authors: Teng-Kuang
authors: TK
authors: Yeh
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, 35053, Taiwan.
authors: Shu-Yu
authors: SY
authors: Lin
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, 35053, Taiwan.
authors: Li-Chin
authors: LC
authors: Ou
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, 35053, Taiwan.
authors: Shu-Chun
authors: SC
authors: Chen
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, 35053, Taiwan.
authors: Wan-Ting
authors: WT
authors: Chang
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, 35053, Taiwan.
authors: Hsiao-Fu
authors: HF
authors: Chang
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, 35053, Taiwan.
authors: Zih-Huei
authors: ZH
authors: Wu
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, 35053, Taiwan.
authors: Chih-Chien
authors: CC
authors: Hsieh
authors: Department of Pharmacology, University of Minnesota, Medical School, Minneapolis, MN, 55455, USA.
authors: Ping-Yee
authors: PY
authors: Law
authors: Department of Pharmacology, University of Minnesota, Medical School, Minneapolis, MN, 55455, USA.
authors: Horace H
authors: HH
authors: Loh
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, 35053, Taiwan.
authors: Chuan
authors: C
authors: Shih
authors: Institute of Biotechnology and Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan. Electronic address: yklai@life.nthu.edu.tw.
authors: Yiu-Kay
authors: YK
authors: Lai
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, 35053, Taiwan; The PhD Program for Neural Regenerative Medicine, Taipei Medical University, Taipei, 110, Taiwan. Electronic address: bau9763@bp.nhri.org.tw.
authors: Shiu-Hwa
authors: SH
authors: Yeh
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, 35053, Taiwan. Electronic address: shueng@nhri.org.tw.
authors: Shau-Hua
authors: SH
authors: Ueng
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000378:metabolism; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism; D008297:Male; D051379:Mice; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D017450:Receptors, Opioid, mu / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D001549:Benzamides; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D017450:Receptors, Opioid, mu; D000262:Adenylyl Cyclases
keywords: Anti-nociceptive effects; Blood-brain barrier; Penetration; Structure-activity relationship; Tail-flick test; κ-opioid receptor agonist; μ-opioid receptor agonist