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; pyramidalneurons of the CA1 zone of the hippocampus were used to study NMDA-and CI-AMPA-receptors. Cell isolation was performed by vibrodissociation; currentswere recorded by whole-cell patch-clamp method. All the studiedcompounds at a concentration of 100 µM inhibited NMDA-receptors(≥30%), while CI-AMPA receptors currents were inhibited by onlyfour compounds: DAB-8, DAB-12, DAB-19, and DAB-32. DAB-8, DAB-12and DAB-32 have a 4-substituted phenacyl group at the nitrogen atomN¹¹ with an electronegative fluorine atomin 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-benzylgroup at atom N¹¹ with a bulky tert-butylsubstituent 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 bothNMDA- and CI-AMPA-receptors: IC₅₀ valueswere 11.0 ± 1.6 µM and 15.4 ± 1.4 µM, respectively. Such an abilityto inhibit both NMDA- and CI-AMPA-receptors at such concentrationsis quite remarkable. Based on previous data on the neuropsychotropiceffects of DAB-19, we put forward hypothesis about its possibleanticonvulsant 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 furtherdevelopment of effective anticonvulsants.