神経活性化合物の開発を可能にしたsp<sup>3</sup>骨格のハイブリッド戦略

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  • 及川 雅人
    横浜市立大学大学院生命ナノシステム科学研究科
  • 塚本 俊太郎
    横浜市立大学大学院生命ナノシステム科学研究科
  • 諸熊 賢治
    横浜市立大学大学院生命ナノシステム科学研究科
  • 入江 樂
    横浜市立大学大学院生命ナノシステム科学研究科
  • 生駒 実
    株式会社スコヒアファーマ　創薬化学研究所

書誌事項

タイトル別名
  • Hybrid Strategy of sp<sup>3</sup>-Rich Scaffolds for Neuroactive Agents
  • 神経活性化合物の開発を可能にしたsp³骨格のハイブリッド戦略
  • シンケイ カッセイ カゴウブツ ノ カイハツ オ カノウ ニ シタ sp ³ コッカク ノ ハイブリッド センリャク

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説明

<p>By a hybrid design of naturally derived excitatory amino acids, dysiherbaines and kainic acid, we have successfully developed a series of artificial glutamate analogs with sp3-rich scaffold via domino Ugi/Diels-Alder reaction, and domino metathesis reaction of oxanorbornenes as key steps. All of the first-generation analogs were found to be neuronally active upon mice intracerebroventricular injection. As the second-generation analogs, we then synthetically modified the heterotricyclic structure, and found that analogs with a carbonyl group on the A-ring still keep the original activity of the first-generation analogs. Structural modification of the second-generation analogs by diversity-oriented reactions such as multicomponent Prins-Ritter reaction was furthermore studied to improve the activity profiles. Electrophysiological studies have identified IKM-159 of the second-generation analogs as an antagonist selective to AMPA-type ionotropic glutamate receptor. The molecular interactions were clarified from crystallographic studies of IKM-159 in complex with GluA2 ligand-binding domain (LBD). From the structure-activity relationships and the structural insights of the complex, a new structural design is proposed herein for neuronally active agents with improved potency and selectivity. We also propose here that generation of sp3-rich scaffold by hybrid strategy of known bioactive molecules would be of use for discovery of artificial bioactive agents with novel activity profiles.</p>

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