YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
レチノイド アンタゴニスト
梅宮 広樹影近 弘之深澤 弘志橋本 祐一首藤 紘一
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1996 年 116 巻 12 号 p. 928-941

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Retinoids, retinoic acid and its bioisosters, regulate many biological functions such as cell differentiation, proliferation and embryonic development in vertabrates, through binding to and activating their specific nuclear receptors. There are two classes of nuclear receptors for retinoids, retinoic acid receptors (RARα, β, γ) and retinoid X receptors (RXRα, β, γ). Several retinoid antagonists, which bind to but not activate RARs, have been reported. Among them, 4-(5H-7, 8, 9, 10-tetrahydro-5, 7, 7, 10, 10-pentamethylbenzo [e] naphtho [2, 3-b] [1, 4] diazepin-13-yl) benzoic acid (LE135, 20) is a RARβ-selective retinoid antagonist. Structure-activity relationships of LE135 (20) showed that the naphthalenyl analogs [LE540 (21) and LE550 (22)] are more potent retinoid antagonists in HL-60 assay. Contrary to the antagonistic activity of LE135 (20), an isomer of LE135 (20), 4-[5H-2, 3-(2, 5-dimethyl-2, 5-hexano)-5-methyldibenzo-[b, e] [1, 4] diazepin-11-yl) benzoic acid (HX600, 39) enhanced the activities of retinoids. Although the synergistic activity of HX600 (39) can be explained by the binding to RXRs and the further activation of RAR/RXR heterodimer activated by retinoid (RAR ligand), the significantly different biological character of HX600 (39) from the typical RXR-selective ligand suggested the possibility of the participation of other nuclear receptors or cofactors in the retinoid synergism.

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