Synthesis and modulatory activity of 3-acetyl-7-(benzofuran-5-carbonyl)-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-one on AMPA receptors

3-Acetyl-7-(benzofuran-5-carbonyl)-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-one belonging to a previously unknown class of unsymmetrical N,N'-diacyl-substituted 1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-ones has been synthesized. The key step in its synthesis involves a desymmetrization of the parent diamine by selective monoacetylation at a lower reaction temperature. In vitro assays by means of electrophysiological patch clamp technique revealed a high positive modulatory effect on the kainate-induced currents in Purkinje neurons in a wide concentration range from 10-11 to 10-6 M. Molecular dynamics simulations have confirmed the putative single and dual binding modes of the title compound in the positive allosteric modulator site of the AMPA (alpha-amino-3-hydroxy-5-methyl- 4-isoxazolepropionic acid) glutamate receptors. These results indicate that it could potentially serve as a lead compound for the development of broad-spectrum drugs for prevention and treatment of neurodegenerative diseases.