Design and synthesis of novel anti-hyperalgesic agents based on 6-prenylnaringenin as the T-type calcium channel blockers.

Autor: Du Nguyen H; Graduate School of Innovative Life Science, University of Toyama, Toyama 930-8555, Japan., Okada T; Graduate School of Innovative Life Science, University of Toyama, Toyama 930-8555, Japan., Kitamura S; Faculty of Engineering, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan., Yamaoka S; Faculty of Pharmacy, Kindai University, Higashi-Osaka 577-8502, Japan., Horaguchi Y; Faculty of Pharmacy, Kindai University, Higashi-Osaka 577-8502, Japan., Kasanami Y; Faculty of Pharmacy, Kindai University, Higashi-Osaka 577-8502, Japan., Sekiguchi F; Faculty of Pharmacy, Kindai University, Higashi-Osaka 577-8502, Japan., Tsubota M; Faculty of Pharmacy, Kindai University, Higashi-Osaka 577-8502, Japan., Yoshida S; Faculty of Science and Engineering, Kindai University, Higashi-Osaka 577-8502, Japan., Nishikawa H; Faculty of Pharmacy, Kindai University, Higashi-Osaka 577-8502, Japan., Kawabata A; Faculty of Pharmacy, Kindai University, Higashi-Osaka 577-8502, Japan., Toyooka N; Graduate School of Innovative Life Science, University of Toyama, Toyama 930-8555, Japan; Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan. Electronic address: toyooka@eng.u-toyama.ac.jp.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2018 Aug 15; Vol. 26 (15), pp. 4410-4427. Date of Electronic Publication: 2018 Jul 19.
DOI: 10.1016/j.bmc.2018.07.023
Abstrakt: Since 6-prenylnaringenin (6-PNG) was recently identified as a novel T-type calcium channel blocker with the IC 50 value around 1 µM, a series of flavanone derivatives were designed, synthesized and subsequently evaluated for T-channel-blocking activity in HEK293 cells transfected with Ca v 3.2 T-type channels using a patch-clamp technique. As a result, several new flavanones blocked Ca v 3.2-dependent T-currents more potently than 6-PNG. In the synthesized compounds, 6-(3-ethylpent-2-enyl)-5,7-dihydroxy-2-(2-hydroxyphenyl)chroman-4-one 8j, 6-(3-ethylpent-2-enyl)-5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one 11b, 6-(2-cyclopentylideneethyl)-5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one 11d, and 6-(2-Cyclopentylethyl)-5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one 12c were more potent blocker than 6-PNG with the IC 50 value of 0.39, 0.26, 0.46, and 0.50 µM, respectively. Among the above four derivatives, the compound 8j provided the best result in the in vivo experiments; i.e. systemic administration of 8j at the minimum dose completely restored neuropathic pain induced by partial sciatic nerve ligation in mice.
(Copyright © 2018 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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