Characterization of a New Positive Allosteric Modulator of AMPA Receptors - PAM-43: Specific Binding of the Ligand and its Ability to Potentiate AMPAR Currents

Author(s): Tatiana V. Vyunova*, Lioudmila A. Andreeva, Konstantin V. Shevchenko, Vladimir V. Grigoriev, Vladimir A. Palyulin, Mstislav I. Lavrov, Ekaterina V. Bondarenko, Elena E. Kalashnikova, Nikolay F. Myasoedov

Journal Name: Current Molecular Pharmacology

Volume 13 , Issue 3 , 2020

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Graphical Abstract:


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 radioligand.

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 molecular activity.

Keywords: Glutamate receptor, allosteric modulation, positive allosteric modulator (PAM), AMPA, NMDA, radioligand, [3H]PAM, AMPAR currents.

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Article Details

Year: 2020
Page: [216 - 223]
Pages: 8
DOI: 10.2174/1874467213666200303140834
Price: $65

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