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Convenient Retinoid X Receptor Binding Assay Based on Fluorescence Change of the Antagonist NEt-C343
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-12-30 , DOI: 10.1021/acs.jmedchem.0c01883 Kayo Yukawa-Takamatsu 1 , Yifei Wang 1 , Masaki Watanabe 1 , Yuta Takamura 1 , Michiko Fujihara 1, 2 , Mariko Nakamura-Nakayama 1 , Shoya Yamada 1, 3 , Shota Kikuzawa 1 , Makoto Makishima 4 , Mayu Kawasaki 5 , Sohei Ito 5 , Shogo Nakano 5 , Hiroki Kakuta 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-12-30 , DOI: 10.1021/acs.jmedchem.0c01883 Kayo Yukawa-Takamatsu 1 , Yifei Wang 1 , Masaki Watanabe 1 , Yuta Takamura 1 , Michiko Fujihara 1, 2 , Mariko Nakamura-Nakayama 1 , Shoya Yamada 1, 3 , Shota Kikuzawa 1 , Makoto Makishima 4 , Mayu Kawasaki 5 , Sohei Ito 5 , Shogo Nakano 5 , Hiroki Kakuta 1
Affiliation
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Retinoid X receptor (RXR) modulators (rexinoids) are considered to have therapeutic potential for multiple diseases, such as Alzheimer’s disease and Parkinson’s disease. To overcome various disadvantages of prior screening methods, we previously developed an RXR binding assay using a fluorescent RXR ligand, CU-6PMN (4). However, this ligand binds not only at the ligand-binding domain (LBD) but also at the dimer–dimer interface of hRXRα. Here, we present a new fluorescent RXR antagonist 6-[N-ethyl-N-(5-isobutoxy-4-isopropyl-2-(11-oxo-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f]pyrido[3,2,1-ij]quinoline-10-carboxamido)phenyl)amino]nicotinic acid (NEt-C343, 7), which emits strong fluorescence only when bound to the RXR-LBD. It allows us to perform a rapid, simple, and nonhazardous binding assay that does not require bound/free separation and uses a standard plate reader. The obtained Ki values of known compounds were correlated with the Ki values obtained using the standard [3H]9cis-retinoic acid assay. This assay should be useful for drug discovery as well as for research on endocrine disruptors, functional foods, and natural products.
中文翻译：
基于拮抗剂NEt-C343荧光变化的便捷类维生素A X受体结合测定
类维生素A X受体（RXR）调节剂（类维生素A）被认为具有治疗多种疾病的潜力，例如阿尔茨海默氏病和帕金森氏病。为了克服现有筛选方法的各种缺点，我们先前开发了使用荧光RXR配体CU-6PMN（4）的RXR结合测定。但是，该配体不仅在配体结合域（LBD）上结合，而且在hRXRα的二聚体-二聚体界面上结合。这里，我们提出一个新的荧光RXR拮抗剂6- [ Ñ乙基Ñ - （5-异丁氧基-4-异丙基-2-（11-氧代- 2,3,6,7-四氢-1- ħ，5 ħ， 11 H-吡喃基[2,3- f ]吡啶基[3,2,1- ij]喹啉-10-甲酰氨基）苯基）氨基]烟酸（NET-C343，7），其发射只有当结合于RXR-LBD强的荧光。它使我们能够执行快速，简单且无害的结合测定，不需要结合/自由分离，而使用标准的酶标仪。将获得的已知化合物的K i值与使用标准[ 3 H] 9顺式-视黄酸测定法获得的K i值相关。该测定法对于药物发现以及内分泌干扰物，功能食品和天然产物的研究均应有用。
更新日期：2021-01-14
中文翻译：
基于拮抗剂NEt-C343荧光变化的便捷类维生素A X受体结合测定
类维生素A X受体（RXR）调节剂（类维生素A）被认为具有治疗多种疾病的潜力，例如阿尔茨海默氏病和帕金森氏病。为了克服现有筛选方法的各种缺点，我们先前开发了使用荧光RXR配体CU-6PMN（4）的RXR结合测定。但是，该配体不仅在配体结合域（LBD）上结合，而且在hRXRα的二聚体-二聚体界面上结合。这里，我们提出一个新的荧光RXR拮抗剂6- [ Ñ乙基Ñ - （5-异丁氧基-4-异丙基-2-（11-氧代- 2,3,6,7-四氢-1- ħ，5 ħ， 11 H-吡喃基[2,3- f ]吡啶基[3,2,1- ij]喹啉-10-甲酰氨基）苯基）氨基]烟酸（NET-C343，7），其发射只有当结合于RXR-LBD强的荧光。它使我们能够执行快速，简单且无害的结合测定，不需要结合/自由分离，而使用标准的酶标仪。将获得的已知化合物的K i值与使用标准[ 3 H] 9顺式-视黄酸测定法获得的K i值相关。该测定法对于药物发现以及内分泌干扰物，功能食品和天然产物的研究均应有用。
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