Аннотация:The glutamate receptors are of crucial importance in CNS functioning. Among the substances acting on the glutamatergic system, the most promising are allosteric modulators of AMPA and KA receptors.1 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. PAMs of AMPA receptor reveal such neurophysiological effects as significant increase of nerve growth factors expression as well as induction of long-term potentiation of synaptic excitation, considered as a substrate for learning and memory. This makes them privileged compounds for the development of nootropic and neuroprotective agents. The negative modulators of AMPA receptors can be employed as antiepileptic drugs. The de novo design of AMPA receptor modulators using previously refined receptor models was supplemented in our work with molecular dynamics simulation of the modulator-agonist-receptor complexes for various possible receptor binding sites. The Molecular Field Topology Analysis (MFTA) QSAR technique 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 as well as predicted ADMET parameters served as useful additional filters. That allowed us to find a series of new positive and negative highly potent allosteric modulators based on several new scaffolds. They include novel tricyclic derivatives of bispidine, substituted bis(pyrimidines) and bis-amides with various linkers/spacers. Convenient synthetic approaches were elaborated and scaled-up for the designed compounds. Electrophysiological patch clamp in vitro experiments have demonstrated the pronounced influence of the studied compounds in sub-nanomolar concentrations on the kainate-induced currents recorded for Purkinje neurons from rat cerebellum. The in vivo studies based on behavioral models have shown cognition-enhancing properties for the designed positive modulators. The combinations of these properties with low toxicity allowed several compounds to successfully pass preclinical studies. This study was supported by the Russian Science Foundation, grant No. 22-15-00041.
