Dr Karel Vales, National Institute of Mental Health; Dr Martin Horak, Academy of Science; Dr Jan Korabecny, Biomedical Research Center; Dr Ondrej Soukup, Biomedical Research Center; Dr Kamil Musilek, University Hradec Kralove
Transfer Technology Office, National Institute of Mental Health
The aim is the design, synthesis and biological testing of structurally different groups of compounds with a dual effect modulation of the cholinergic or GABAergic and glutamatergic system. That can be used in treatment and research into epileptic encephalopathies, affective disorders or neurodegenerative disorders.
With regard to the numerous etiology of CNS disorders, in recent years research in the field of the development of pharmaceuticals has been focused on such structures that are capable of hitting a number of targets simultaneously. A combination of pharmaceuticals in clinical practice is not a new phenomenon. In particular, MMT (multiple-medication therapy) is used, which is a combination of a number of medicaments used for a specific disorder with a different mechanism of effect, and “multiple-compound medication” (MCM), in which a number of different medicaments are incorporated into a single pharmaceutical form. From the perspective of the development of new pharmaceuticals, an interesting strategy is based on the assumption that a single compound would be capable of hitting a number of targets simultaneously. This concerns multi-target-directed ligands (MTDLs). One of the most commonly used approaches in this area is the modification of the molecular structures of acetylcholinesterase (AchE) inhibitors, so as to provide supplementary biological properties suitable for the treatment of neurodegeneration. In this case, it shall concern a combination of acetylcholinesterase (AchE) inhibitor or GABAa positive potentiation and negative modulation of the N-methyl-D-aspartate receptors (NMDAR). On the basis of the preliminary data, new molecules will be designed, synthesized and in vivo tested, influencing both targets simultaneously. These dually active substances describe promising results in the animal models of CNS disorders. The combination of these effects is thus highly promising both from the perspective of basic research into new potential medicaments and with regard to their potential applicability.
Psychiatry, neurology, neurodevelopmental diseases
preclinical, animal models
The neuroprotective ability of the compounds to prevent or treat neuronal damage caused by the NMDAr overstimulation was confirmed by the permanent lesion of hippocampus induced by a microinjection of NMDA.
Efficacy in animal models of neuropsychiatric diseases was tested in the MK-801-induced schizophrenia attack model.
We also tested the effect of the molecules in well-established anxiety tests.
Furthermore, we have also studied behavioral effects in intact animals - Anticonvulsion effect in PTZ model is planned - Olfactory bulbectomized rat as a model of depression is planned
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