國家衛生研究院 NHRI:Item 3990099045/9983

NHRI > Institute of Biotechnology and Pharmaceutical Research > Shau-Hua Ueng > Periodical Articles > Item 3990099045/9983

Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/9983

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
Authors:	Chen, SR;Ke, YY;Yeh, TK;Lin, SY;Ou, LC;Chen, SC;Chang, WT;Chang, HF;Wu, ZH;Hsieh, CC;Law, PY;Loh, HH;Shih, C;Lai, YK;Yeh, SH;Ueng, SH
Contributors:	Institute of Biotechnology and Pharmaceutical Research
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.
Date:	2017-01
Relation:	European Journal of Medicinal Chemistry. 2017 Jan;126:202-217.
Link to:	http://dx.doi.org/10.1016/j.ejmech.2016.09.003
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0223-5234&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:000396804600020
Cited Times(Scopus):	http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84992549305
Appears in Collections:	[Shau-Hua Ueng] Periodical Articles [Shiu-Hwa Yeh] Periodical Articles [Chuan Shih(2014-2017)] Periodical Articles [Teng-Kuang Yeh] Periodical Articles [Shu-Yu Lin] Periodical Articles

Files in This Item:

File	Description	Size	Format
SDO0223523416307310.pdf.pdf		1858Kb	Adobe PDF	686	View/Open

Loading...