Ligands of the AMPA-subtype glutamate receptors: mechanisms of action and novel chemotypes

Ionotropic glutamate receptors of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype play a key role in synaptic plasticity representing one of the mechanisms for learning and memory formation. They can also serve as targets for the development of novel classes of pharmaceuticals for the treatment or substantive correction of many serious neurodegenerative and psychoneurological disorders. The search and studies of various types of AMPA receptor ligands attract considerable attention from academic organizations and pharmaceutical companies all over the world. This review mainly focuses on recent advances in this field. The architecture and operational mechanism of the receptor as well as its major binding sites and ligand types are considered. Special attention is paid to the studies of mechanisms of action and novel chemotypes of AMPA receptor agonists and competitive antagonists, positive and negative allosteric modulators, auxiliary protein-dependent allosteric modulators, and ion channel blockers.

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AMPA Receptor Antagonist CFM-2 Decreases Survivin Expression in Cancer Cells

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520618666180228123406 ◽

2018 ◽

Vol 18 (4) ◽

pp. 591-596 ◽

Cited By ~ 1

Author(s):

Domingo Sanchez Ruiz ◽

Hella Luksch ◽

Marco Sifringer ◽

Achim Temme ◽

Christian Staufner ◽

...

Keyword(s):

Cell Survival ◽

Receptor Antagonist ◽

Cancer Cells ◽

Glutamate Receptors ◽

Cancer Cell ◽

Ampa Receptor ◽

Ampa Receptors ◽

Survivin Expression ◽

Ampa Receptor Antagonist ◽

Cancer Cell Survival

Background: Glutamate receptors are widely expressed in different types of cancer cells. α-Amino-3- hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors are ionotropic glutamate receptors which are coupled to intracellular signaling pathways that influence cancer cell survival, proliferation, and migration. Blockade of AMPA receptors by pharmacologic compounds may potentially constitute an effective tool in anticancer treatment strategies. Method: Here we investigated the impact of the AMPA receptor antagonist CFM-2 on the expression of the protein survivin, which is known to promote cancer cell survival and proliferation. We show that CFM-2 inhibits survivin expression at mRNA and protein levels and decreases the viability of cancer cells. Using a stably transfected cell line which overexpresses survivin, we demonstrate that over-expression of survivin enhances cancer cell viability and attenuates CFM-2–mediated inhibition of cancer cell growth. Result: These findings point towards suppression of survivin expression as a new mechanism contributing to anticancer effects of AMPA antagonists.

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QSAR Study of Anticonvulsant Negative Allosteric Modulators of the AMPA Receptor

Journal of Medicinal Chemistry ◽

10.1021/jm0310838 ◽

2004 ◽

Vol 47 (7) ◽

pp. 1860-1863 ◽

Cited By ~ 14

Author(s):

Antonio Macchiarulo ◽

Laura De Luca ◽

Gabriele Costantino ◽

Maria Letizia Barreca ◽

Rosaria Gitto ◽

...

Keyword(s):

Ampa Receptor ◽

Allosteric Modulators ◽

Qsar Study

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NMDA and AMPA Receptor Autoantibodies in Brain Disorders: From Molecular Mechanisms to Clinical Features

Cells ◽

10.3390/cells10010077 ◽

2021 ◽

Vol 10 (1) ◽

pp. 77

Author(s):

Fabrizio Gardoni ◽

Jennifer Stanic ◽

Diego Scheggia ◽

Alberto Benussi ◽

Barbara Borroni ◽

...

Keyword(s):

Glutamate Receptors ◽

Ampa Receptor ◽

Molecular Mechanisms ◽

Clinical Symptoms ◽

In Vivo Studies ◽

Ionotropic Glutamate Receptors ◽

Brain Disorders ◽

Functional Impairments ◽

Different Types

The role of autoimmunity in central nervous system (CNS) disorders is rapidly expanding. In the last twenty years, different types of autoantibodies targeting subunits of ionotropic glutamate receptors have been found in a variety of patients affected by brain disorders. Several of these antibodies are directed against NMDA receptors (NMDAR), mostly in autoimmune encephalitis, whereas a growing field of research has identified antibodies against AMPA receptor (AMPAR) subunits in patients with different types of epilepsy or frontotemporal dementia. Several in vitro and in vivo studies performed in the last decade have dramatically improved our understanding of the molecular and functional effects induced by both NMDAR and AMPAR autoantibodies at the excitatory glutamatergic synapse and, consequently, their possible role in the onset of clinical symptoms. In particular, the method by which autoantibodies can modulate the localization at synapses of specific target subunits leading to functional impairments and behavioral alterations has been well addressed in animal studies. Overall, these preclinical studies have opened new avenues for the development of novel pharmacological treatments specifically targeting the synaptic activation of ionotropic glutamate receptors.

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