ANALYSIS OF THE PROPERTIES OF NEW PAM AMPA RECEPTORS BASED ON 3,7-DIAZABICYCLO[3.3.1]NONANE FRAME

The development study was a continuation research of the action mechanism of the developed innovative pharmaceutical substance based on the 3,7-diazabicyclo[3.3.1]nonane derivative, which belongs to the class of AMPA receptor modulators. A significant amount of data has been accumulated on the pharmacology and mechanism of action of glutamate receptors, which are widely represented in the central nervous system of animals and humans. AMPA receptors are ionotropic and, along with receptors of other subtypes, are involved in glutamate-mediated excitatory signaling. Several subunits (GluRAl-GluRA4) are distinguished in the structure of the AMPA receptor, which exhibit different sensitivity to receptor ligands. Modulators of AMPA receptors exhibiting pharmacological activity were studied: derivatives of pyrrolidinones, benzothiadiazine dioxides, benzylpiperidines and biarylpropylsulfonamides. The aim of this study was to analyze the therapeutic potential of the mechanism of action of new positive allosteric modulators of AMPA receptors based on the derivative of 3,7-diazabicyclo[3.3.1]nonane framework. Based on the analysis of the spatial structure of the AMPA receptor, its complexes with the known PAM AMPA, and the results of their molecular docking, it was shown that compounds based on the tricyclic derivative 3,7-diazabicyclo[3.3.1]nonans bind to AMPA receptors at a fundamentally different location than ampakins from other known PAM AMPA groups. These compounds have the ability to facilitate AMPA-mediated glutamatergic neurotransmission to the central nervous system. According to the analyzed studies, AMPA receptor modulators are able to accelerate the period of convalescence after neurodegenerative states, exhibit an antidepressant effect, and have neuroprotective properties. The discovery of the ability of positive allosteric modulators of the AMPA receptor to induce the expression of neurotrophic factors BDNF and NGF, triggering the mechanisms responsible for the survival of existing functioning neurons, as well as growth and differentiation, the formation of new synapses makes the development of new drugs based on tricyclic derivatives of 3,7-diazabicyclo[3.3.1]nonane is especially promising for use in the later stages of post-stroke rehabilitation.