ИСТИНА

Positive allosteric modulators (PAMs) of AMPA receptors (one of types of ionotropic glutamate receptors) have a significant influence on learning and memory consolidation. It is also shown in experiments that the ion currents caused by such modulators and further postsynaptic membrane depolarization launch the mechanism of gene expression responsible for the synthesis of NGF (nerve growth factor) and BDNF (brain-derived neurotrophic factor). Thus the drugs having this mechanism of action could be efficient for the treatment of neurodegenerative diseases. In this report the techniques are considered for computer-aided design of AMPA receptor modulators based on new scaffolds as well as the approaches to their synthesis and the results of physiological activity studies. The molecular dynamics simulations for a series of AMPA receptor PAMs bound on the interface between two glutamate-binding domains have demonstrated a good correlation of the MM-GBSA and MM-PBSA binding energies with the experimental pEC50 values. The Molecular Field Topology Analysis (MFTA) QSAR method developed by us was quite helpful in the modeling of ligand selectivity and multi-target activity in terms of local properties such as the atomic charges, group van der Waals radii, and local lipophilicity. In addition, the 3D QSAR and pharmacophore models of the AMPA receptor PAMs have been constructed. The virtual screening of large compound libraries using the above mentioned models as the filters as well as the de novo design of the structures fitting the PAM binding site and based on new scaffolds allowed us to find a series of novel highly potent positive allosteric modulators of AMPA receptors. Several compounds are on the final stages of preclinical studies. The modulators found have a unique combination of properties including picomolar activity and very low toxicity.