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

Eur J Med Chem. 2017 Jan 27:126:202-217. doi: 10.1016/j.ejmech.2016.09.003.

Sheng-Ren Chen ¹, Yi-Yu Ke ², Teng-Kuang Yeh ², Shu-Yu Lin ², Li-Chin Ou ², Shu-Chun Chen ², Wan-Ting Chang ², Hsiao-Fu Chang ², Zih-Huei Wu ², Chih-Chien Hsieh ², Ping-Yee Law ³, Horace H Loh ³, Chuan Shih ², Yiu-Kay Lai ⁴, Shiu-Hwa Yeh ⁵, Shau-Hua Ueng ⁶

Affiliations

1 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.
2 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, 35053, Taiwan.
3 Department of Pharmacology, University of Minnesota, Medical School, Minneapolis, MN, 55455, USA.
4 Institute of Biotechnology and Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan. Electronic address: yklai@life.nthu.edu.tw.
5 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.
6 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, 35053, Taiwan. Electronic address: shueng@nhri.org.tw.

PMID: 27776274 DOI: 10.1016/j.ejmech.2016.09.003

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 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.

Keywords

Anti-nociceptive effects; Blood-brain barrier; Penetration; Structure-activity relationship; Tail-flick test; κ-opioid receptor agonist; μ-opioid receptor agonist.

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