Basic information

Investigator: RNDr. Karel Valeš, PhD.
Main recipient: National Institute of Mental Health (NIMH)
Co-recipient: Institute of Experimental Medicine of the AV ČR, v. v. i., VŠCHT
Research period:  1/5/2024 - 31/12/2027
Total budget: 15,873,000 CZK
NIMH budget: 5,821,000 CZK
Supported by: Czech Health Research Council (AZV ČR)

Annotation

The hypothesis of the project is based on preliminary results, which indicate that the diarylethylaminated derivative of MXP has a specific mechanism of efficacy, kinetics, and blocking of the open NMDAR channel, which appropriately modulates synaptic and extrasynaptic NMDAR. This modulation is expected to lead to an antidepressant effect during in vivo testing without significant side effects. Several research steps will be taken to achieve the project's goal. First, state-of-the-art molecular modeling methods and molecular dynamics-based approaches will be used for computational screening and identification of structures that can bind to NMDAR with high affinity. The identified structures with the highest pharmacological potential will be synthesized in the laboratory. The newly synthesized compounds will undergo in vitro testing. In the in vitro phase, the modulatory effect of the newly developed substances will be studied using electrophysiological techniques. This characterization will include examining the molecular mechanisms of action of these substances on NMDAR expressed in cell cultures and brain hippocampal slices obtained from animals with experimentally induced depressive illness. Given the therapeutic potential of the tested substances, promising molecules will then be further evaluated for their antidepressant effects on animal models. Depression-like behavior will be induced in animals using olfactory bulbectomy. The antidepressant effects of the synthesized NMDAR modulators will be compared to the effects of clinically used ketamine. Overall, the aim of the project is to advance the understanding of the mechanism of action and research and development of new molecules that can selectively modulate NMDAR and exhibit antidepressant effects in animal models, offering new possibilities for depression pharmacotherapy.