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Novel Positive Allosteric Modulators of AMPA Receptors Based on 3,7-Diazabicyclo[3.3.1]nonane Scaffold.
Lavrov, Mstislav I; Karlov, Dmitry S; Voronina, Tatiana A; Grigoriev, Vladimir V; Ustyugov, Aleksey A; Bachurin, Sergey O; Palyulin, Vladimir A.
Affiliation
  • Lavrov MI; Department of Chemistry, Lomonosov Moscow State University, Moscow, Russian Federation, 119991.
  • Karlov DS; Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, Moscow Region, Russian Federation, 142432.
  • Voronina TA; Department of Chemistry, Lomonosov Moscow State University, Moscow, Russian Federation, 119991.
  • Grigoriev VV; Center for Computational and Data-Intensive Science and Engineering, Skolkovo Institute of Science and Technology, 3 Nobel St., Moscow, Russian Federation, 121205.
  • Ustyugov AA; Federal State Budgetary Institution "Research Zakusov Institute of Pharmacology", Moscow, Russian Federation, 125315.
  • Bachurin SO; Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, Moscow Region, Russian Federation, 142432.
  • Palyulin VA; Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, Moscow Region, Russian Federation, 142432.
Mol Neurobiol ; 57(1): 191-199, 2020 Jan.
Article in En | MEDLINE | ID: mdl-31515692
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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Receptors, AMPA / Alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Excitatory Amino Acid Antagonists / Hippocampus Limits: Animals Language: En Journal: Mol Neurobiol Journal subject: BIOLOGIA MOLECULAR / NEUROLOGIA Year: 2020 Document type: Article Country of publication: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Receptors, AMPA / Alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Excitatory Amino Acid Antagonists / Hippocampus Limits: Animals Language: En Journal: Mol Neurobiol Journal subject: BIOLOGIA MOLECULAR / NEUROLOGIA Year: 2020 Document type: Article Country of publication: United States