Enhancer of neuroactive steroids biosynthesis: search for agents potentially repositioned as a anxiolytic drugs

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K15304
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Tokyo University of Science
• Principal Investigator: Kusunose Shoichi 東京理科大学, 薬学部薬学科, 助教 (60868470)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Keywords: 神経活性ステロイド / 抗不安薬 / アロプレグナノロン / スクリーニング / ドラッグリポジショニング / アリールオキシプロパンアミン

Outline of Final Research Achievements

We developed a method to evaluate differences in the amount of allopregnanolone (AP) produced by cultured cells with and without drug treatment by combining high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) with derivatization using Girard's reagent P and its isotopologue (2H5-Girard's reagent P). We also developed a highly sensitive and reliable LC/ESI-MS/MS/MS method for determination AP levels in rat brain based on isotope-coded derivatization. Using these methods, we found for the first time that duloxetine, dapoxetine, and propranolol promote AP biosynthesis in the rat brains, indicating that the increase in AP level in the brain may be involved in the anxiolytic effects of these drugs

Free Research Field

分析化学

Academic Significance and Societal Importance of the Research Achievements

本研究で新たにAP生合成促進作用が見出されたデュロキセチン，ダポキセチン，プロプラノロールと，既にAP生合成促進作用が知られている薬剤 (フルオキセチンやパロキセチン) は共通した部分構造 (アリールオキシプロパンアミン構造) を有しており，この構造がAP合成に関わる酵素の活性化に関与する可能性が示唆された．
また，本研究開発された培養細胞を用いたスクリーニング系，ラット脳内AP分析法は，今後のAP生合成促進を基盤とした新たな抗不安薬探索の推進に寄与するものと期待される．