Design and synthesis of novel anti-hyperalgesic agents based on 6-prenylnaringenin as the T-type calcium channel blockers. Issue 15 (15th August 2018)

• Record Type: Journal Article
• Authors: Du Nguyen, Huy; Okada, Takuya; Kitamura, Shun; Yamaoka, Sakura; Horaguchi, Yamato; Kasanami, Yoshihito; Sekiguchi, Fumiko; Tsubota, Maho; Yoshida, Shigeru; Nishikawa, Hiroyuki; Kawabata, Atsufumi; Toyooka, Naoki
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 15(2018)
• Page Start: 4410
• Page End: 4427
• Publication Date: 2018-08-15
• Subjects: 6-Prenylnaringenin -- T-type calcium channel blocker -- Flavanone derivative -- Neuropathic pain -- Mechanical allodynia; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.07.023
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Since 6-prenylnaringenin (6-PNG) was recently identified as a novel T-type calcium channel blocker with the IC50 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 Cav 3.2 T-type channels using a patch-clamp technique. As a result, several new flavanones blocked Cav 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-one8j, 6-(3-ethylpent-2-enyl)-5, 7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one11b, 6-(2-cyclopentylideneethyl)-5, 7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one11d, and 6-(2-Cyclopentylethyl)-5, 7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one12c were more potent blocker than 6-PNG with the IC50 value of 0.39, 0.26, 0.46, and 0.50 µM, respectively. Among the above four derivatives, the compound8j provided the best result in the in vivo experiments; i.e. systemic administration of8j at the minimum dose completely restored neuropathic pain induced by partial sciatic nerve ligation in mice.