Background: Currently, the most dynamic areas in the glutamate receptor system neurobiology
are the identification and development of positive allosteric modulators (PAMs) of glutamate
ionotropic receptors. PAM-based drugs are of great interest as promising candidates for the treatment of
neurological diseases, such as epilepsy, Alzheimer's disease, schizophrenia, etc. Understanding the
molecular mechanisms underlying the biological action of natural and synthetic PAMs is a key point for
modifying the original chemical compounds as well as for new drug design.
Objective: We are trying to elaborate a system of molecular functional screening of ionotropic glutamate
receptor probable PAMs.
Methods: The system will be based on the radioligand - receptor method of analysis and will allow
rapid quantification of new AMPAR probable PAMs molecular activity. We plan to use a tritiumlabeled
analogue of recently elaborated ionotropic GluR probable PAM ([3H]PAM-43) as the main
Results: Here, we characterized the specific binding of the ligand and its ability to potentiate ionotropic
GluR currents. The existence of at least two different sites of [3H]PAM-43 specific binding has been
shown. One of the above sites is glutamate-dependent and is characterized by higher affinity. “Patchclamp”
technique showed the ability of PAM-43 to potentiate ionotropic GluR currents in rat cerebellar
Purkinje neurons in a concentration-dependent manner.
Conclusion: The possibility of using PAM-43 as a model compound to study different allosteric effects
of potential regulatory drugs (AMPAR allosteric regulators) was shown. [3H]PAM-43 based screening
system will allow rapid selection of new AMPAR probable PAM structures and quantification of their