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<p>A synthetic approach was developed for the preparation of the previously unknown target diamide, 3-acetyl-1,5-dimethyl-7-piperonyloyl-3,7-diazabicyclo[3.3.1]nonan-9-one. The desymmetrization of the intermediate diamine was achieved <i>via</i> the kinetic control of the reaction. The <i>in vitro</i> patch clamp assays revealed a high positive modulatory activity of the synthesized compound toward the AMPA receptor in a wide concentration range (from 10<sup>−12</sup> to 10<sup>−6</sup> mol L<sup>−1</sup>), with the maximum potentiation of kainate-induced currents at a concentration of 10<sup>−11</sup> mol L<sup>−1</sup>. Molecular docking and molecular dynamics simulation studies confirmed the putative single and dual binding modes of the target compound in the binding site of the AMPA receptor characteristic of positive allosteric modulators.</p>

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3-Acetyl-1,5-dimethyl-7-piperonyloyl-3,7-diazabicyclo[3.3.1]nonan-9-one: synthesis, structure, and modulation of the AMPA receptor

  • 期刊论文

  • 发表日期：

    2025年5月1日

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  • J. Matthews,
  • E. K. Arsentyeva,
  • P. N. Veremeeva,
  • E. A. Golubeva,
  • M. I. Lavrov,
  • E. V. Radchenko,
  • V. A. Tafeenko,
  • V. L. Zamoyski,
  • V. V. Grigoriev,
  • V. A. Palyulin

摘要

A synthetic approach was developed for the preparation of the previously unknown target diamide, 3-acetyl-1,5-dimethyl-7-piperonyloyl-3,7-diazabicyclo[3.3.1]nonan-9-one. The desymmetrization of the intermediate diamine was achieved via the kinetic control of the reaction. The in vitro patch clamp assays revealed a high positive modulatory activity of the synthesized compound toward the AMPA receptor in a wide concentration range (from 10−12 to 10−6 mol L−1), with the maximum potentiation of kainate-induced currents at a concentration of 10−11 mol L−1. Molecular docking and molecular dynamics simulation studies confirmed the putative single and dual binding modes of the target compound in the binding site of the AMPA receptor characteristic of positive allosteric modulators.