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Novel Positive Allosteric Modulators of AMPA Receptors Based on 3,7-Diazabicyclo[3.3.1]nonane Scaffold

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Abstract

A series of new positive allosteric modulators (PAMs) of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors based on 3,7-diazabicyclo[3.3.1]nonane scaffold have been designed, synthesized, and analyzed. In electrophysiological patch clamp studies, several compounds have demonstrated a sub-nanomolar potency. Compound 4 in in vivo tests showed anti-amnestic properties in the scopolamine-induced model of amnesia in the step-through passive avoidance or maximal electroshock experiments in rats at 0.01 mg/kg showing a significant “dose-response” advantage over memantine. Based on the analysis of the flexible docking results of PAMs, the cyclothiazide-like mechanism of binding mode was suggested as the major site for the interaction with AMPA receptors.

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Abbreviations

PAMs:

positive allosteric modulators

AMPA receptors:

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors

STRA:

step-through passive avoidance

MES:

maximal electroshock

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Acknowledgments

The animal facilities and equipment of the “Centre for Collective Use of IPAC RAS” were used.

Funding

Molecular modeling and docking studies were supported by Russian Science Foundation grant no. 17-15-01455. Biological part of the study was supported by the IPAC RAS State Targets Project no. 0090-2019-0005.

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Author notes

  1. Sergey O. Bachurin and Vladimir A. Palyulin contributed equally to this work.

Authors and Affiliations

  1. Department of Chemistry, Lomonosov Moscow State University, Moscow, Russian Federation, 119991

    Mstislav I. Lavrov, Dmitry S. Karlov & Vladimir A. Palyulin

  2. Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, Moscow Region, Russian Federation, 142432

    Mstislav I. Lavrov, Vladimir V. Grigoriev, Aleksey A. Ustyugov, Sergey O. Bachurin & Vladimir A. Palyulin

  3. Center for Computational and Data-Intensive Science and Engineering, Skolkovo Institute of Science and Technology, 3 Nobel St., Moscow, Russian Federation, 121205

    Dmitry S. Karlov

  4. Federal State Budgetary Institution “Research Zakusov Institute of Pharmacology”, Moscow, Russian Federation, 125315

    Tatiana A. Voronina

Authors
  1. Mstislav I. Lavrov
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  2. Dmitry S. Karlov
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  3. Tatiana A. Voronina
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  4. Vladimir V. Grigoriev
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  5. Aleksey A. Ustyugov
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  6. Sergey O. Bachurin
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  7. Vladimir A. Palyulin
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Corresponding authors

Correspondence to Sergey O. Bachurin or Vladimir A. Palyulin.

Ethics declarations

All experiments were approved by the Institutional Animal Review Board and were conducted in accordance with the Russian law “On Establishing Rules of Good Laboratory Practice” (23.09.2010, no. 708n).

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Lavrov, M.I., Karlov, D.S., Voronina, T.A. et al. Novel Positive Allosteric Modulators of AMPA Receptors Based on 3,7-Diazabicyclo[3.3.1]nonane Scaffold. Mol Neurobiol 57, 191–199 (2020). https://doi.org/10.1007/s12035-019-01768-6

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