Diverse Action of Diazepinobenzimidazole Derivatives on the Glutamatergic Transmission: Structure–Function Study

Abstract One of the problems of modern neuropharmacology is the search for new structures that affect specific targets in the nervous system. Among such promising structures is diazepinobenzimidazole, which includes two privileged subclasses: diazepine and benzimidazole. One of its derivatives, DAB-19, demonstrates a wide range of activities and appears to be very promising. However, the targets of DAB-19 and the molecular mechanisms of its action remain poorly understood. DAB-19 inhibits AMPA- and NMDA-subtypes of glutamate receptors, blocks voltage-gated sodium channels, and enhances spontaneous synaptic release of glutamate. This complex action profile complicates the analysis of action mechanisms. In this study, we investigated the effects of several analogues of DAB-19 to separate the action on different targets by structure–function analysis. We found that the presence of a side chain in diazepinobenzimidazole derivatives is necessary for both stimulating spontaneous release and blocking sodium channels. The presence of a long side chain containing an aromatic ring is critical for stimulating spontaneous release. Compounds with a shorter radical with a saturated ring lose their ability to stimulate spontaneous release but retain their ability to block sodium channels. The results are important for the further targeted design of new compounds that modulate the functions of the central nervous system (CNS).