Search for Inhibitors of Ionotropic Glutamate Receptors in a Series of 2,3,4,5-Tetrahydro[1,3]diazepino[1,2-a]benzimidazole Derivatives

In the present work, 14 new diazepinobenzimidazole derivatives (DAB series) were screened for inhibitory activity against NMDA- and Ca2+-impermeable (CI) AMPA-receptors. Experiments were conducted on isolated Wistar rat neurons; pyramidal neurons of the CA1 zone of the hippocampus were used to study NMDA- and CI-AMPA-receptors. Cell isolation was performed by vibrodissociation; currents were recorded by whole-cell patch-clamp method. All the studied compounds at a concentration of 100 µM inhibited NMDA-receptors (≥30%), while CI-AMPA receptors currents were inhibited by only four compounds: DAB-8, DAB-12, DAB-19, and DAB-32. DAB-8, DAB-12 and DAB-32 have a 4-substituted phenacyl group at the nitrogen atom N11 with an electronegative fluorine atom in the para position (DAB-8 and DAB-32) or without it (DAB-12), whereas the most active compound DAB-19 has a 4-tert-butyl-benzyl group at atom N11 with a bulky tert-butyl substituent in the para position. The most active of them were DAB-12, DAB-19, and DAB-32, which were studied further for their IC50 values. Compound DAB-19 demonstrated the most pronounced activity against both NMDA- and CI-AMPA-receptors: IC50 values were 11.0 ± 1.6 µM and 15.4 ± 1.4 µM, respectively. Such an ability to inhibit both NMDA- and CI-AMPA-receptors at such concentrations is quite remarkable. Based on previous data on the neuropsychotropic effects of DAB-19, we put forward hypothesis about its possible anticonvulsant activity, which was confirmed in the “Pentylenetetrazol Seizure” test. The identification of DAB-19 as a combined antagonist of NMDA- and CI-AMPA-receptors is an important achievement for the further development of effective anticonvulsants.