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

Mol Neurobiol. 2020 Jan;57(1):191-199. doi: 10.1007/s12035-019-01768-6. Epub 2019 Sep 12.

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; Anti-amnestic compounds; Patch clamp; Positive allosteric modulators (PAMs); Scopolamine; Step-through passive avoidance.

MeSH terms

  • Allosteric Regulation / drug effects
  • Animals
  • Benzothiadiazines / pharmacology
  • Excitatory Amino Acid Agonists / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Male
  • Rats, Wistar
  • Receptors, AMPA / metabolism*
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology*

Substances

  • Benzothiadiazines
  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Receptors, AMPA
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • cyclothiazide