Аннотация:Glutamatergic system plays a key role in the functioning of the mammalian central nervous system. The AMPA receptors, an important type of ionotropic glutamate receptors, are attractive targets for the treatment of a number of neurological and psychiatric diseases. The positive allosteric modulators (PAMs) of AMPA receptors as compared to direct agonists are more safe and able to perform the fine tuning of the glutamatergic system since they do not cause any effects in the absence of the natural ligand in the synapse, unlike the direct agonists, the overdose of which can cause the hyperstimulation of CNS glutamatergic system leading to the brain damage. AMPA receptor PAMs are able to improve memory and cognition and could be used for the treatment of dementia, Parkinson’s disease, Alzheimer’s disease and a few other disorders, while negative modulators could be promising agents, e.g., for the treatment of epilepsy.
The molecular modeling of the ligand-receptor interactions of PAMs with the AMPA receptors as well as the molecular dynamics simulations of these systems (with PAMs bound on the interface between two glutamate-binding domains) have demonstrated a good correlation of calculated binding energies with the experimental pEC50 values. The Molecular Field Topology Analysis (MFTA) QSAR method was quite beneficial in the modeling of ligand potency within the series of closely related compounds. The 3D QSAR and pharmacophore models of the AMPA receptor PAMs served as useful additional filters. The combination of these techniques as well as the virtual screening of ZINC compound libraries allowed us to identify and design new scaffolds for PAMs and create the focused libraries of promising PAM structures.
The modelling studies have lead to the development of both positive and negative AMPA receptor modulators with experimentally confirmed potency in electrophysiological studies.
