| Description |
N-methyl-D-aspartate receptors (NMDARs) play an essential role in excitatory neurotransmission in the mammalian brain and are responsible for memory formation and learning. Their physiological importance is underscored by the large number of pathogenic mutations that have been identified in GluN receptor subunits, and which are associated with a variety of diseases, including epilepsy. Our long-term goal is to develop "personalized" compounds for the treatment of specific pathophysiological conditions associated with known pathogenic mutations in GluN subunits. Although FDA-approved pharmacological compounds such as memantine and ketamine that inhibit NMDAR function are currently available, there is still a high demand for the development of additional compounds that act through a different mechanism. The main goal of the work will be to develop new open channel blocker constructs conjugated on a macromolecular carrier, which will specifically modulate the main NMDAR subtypes, GluN1/GluN2A and GluN1/GluN2B, present only in the extrasynaptic regions of mammalian neurons. The task of the work will be to study the effect of the size of the macromolecular carrier and its surface modification by NMDAR inhibitors on the ability to block open channels. We will aim to optimize the physicochemical properties of the constructs, including their solubility and ability to cross the blood-brain barrier, and side effects in vivo to positively pharmacologically modulate behavioral deficits and audiogenic seizures in the GluN2A-N615K knock-in mouse model. As part of the work, close cooperation with the Institute of Experimental Medicine of the Academy of Sciences of the Czech Republic and workplaces abroad is expected. |
