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

  • Mstislav I. Lavrov
  • Dmitry S. Karlov
  • Tatiana A. Voronina
  • Vladimir V. Grigoriev
  • Aleksey A. Ustyugov
  • Sergey O. BachurinEmail author
  • Vladimir A. PalyulinEmail author
Article
  • 13 Downloads

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.

Keywords

3,7-Diazabicyclo[3.3.1]nonanes AMPA receptor Positive allosteric modulators (PAMs) Patch clamp Scopolamine Step-through passive avoidance Anti-amnestic compounds 

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

Notes

Acknowledgments

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

Funding Information

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.

Compliance with Ethical Standards

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).

Supplementary material

12035_2019_1768_MOESM1_ESM.docx (139 kb)
ESM 1 (DOCX 138 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of ChemistryLomonosov Moscow State UniversityMoscowRussian Federation
  2. 2.Institute of Physiologically Active CompoundsRussian Academy of SciencesChernogolovkaRussian Federation
  3. 3.Center for Computational and Data-Intensive Science and EngineeringSkolkovo Institute of Science and TechnologyMoscowRussian Federation
  4. 4.Federal State Budgetary Institution “Research Zakusov Institute of Pharmacology”MoscowRussian Federation

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