Аннотация:Ionotropic glutamate receptors attract a growing attention in the last decades as
promising targets for development of drugs for the treatment of serious neurological and
psychiatric disorders, such as schizophrenia, depression, age-related cognitive and memory
disorders, Parkinson’s disease, Alzheimer’s disease, etc. AMPA receptor positive allosteric
modulators were shown to reveal such neurophysiologic effects as induction of long-term
potentiation of synaptic excitation, considered as a foundation for learning and memory,
and significant increase of nerve growth factors expression, making them promising compounds
for the development of nootropics and neuroprotectors.
Techniques 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 are considered. 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 calculated binding energies with the experimental pEC50 values. The
Molecular Field Topology Analysis (MFTA) QSAR method 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 de novo
design of structures fitting the PAM binding site and based on new scaffolds allowed us to
find novel highly potent positive allosteric modulators of AMPA receptors that have a unique
combination of properties.
