Mgr. Anna Misiachna / Department of Neurochemistry
N-methyl-D-aspartate receptors (NMDARs) belong to a family of ionotropic glutamate receptors that play essential roles in excitatory neurotransmission and synaptic plasticity in the mammalian central nervous system (CNS), and their dysfunction leads to many neuropathological disorders. NMDARs are heterotetramers comprised of GluN1, GluN2A-D, and/or GluN3A-B subunits. Several NMDAR modulators have been used successfully in clinical trials and thus NMDARs are a promising pharmacological target for the treatment of many CNS diseases. Our long-term goal is to develop compounds for treating specific pathophysiological conditions associated with altered NMDARs function. Tacrine (1,2,3,4-Tetrahydro-9-aminoacridine) was the first approved drug for Alzheimer's disease treatment. In collaboration with the Biomedical Research Center in Hradec Kralove and the National Institute of Mental Health in Klecany, we developed a series of 7-methoxyderivatives of tacrine (7-MEOTA) that act on both cholinergic and NMDARs transmission; and 7-phenoxytacrine (7-PhO-THA)-based derivatives that act preferentially on GluN2B-containing NMDARs. Using electrophysiological recordings in HEK293 cells, expressing defined types of NMDARs, we identified the most potent 7-MEOTA derivatives that act in a voltage-dependent manner at GluN1/GluN2A and/or GluN1/GluN2B receptors, as well as 7-PhO-THA-based derivatives preferentially inhibit GluN1/GluN2B receptors over GluN1/GluN2A receptors. Our data indicate that 7-MEOTA and 7-PhO-THA-based derivatives are potentially promising compounds for the treatment of CNS diseases associated with altered NMDAR function including neurodegeneration.