title: AMPA Receptors as Therapeutic Targets for Neurological Disorders.
abstract: Almost every neurological disease directly or indirectly affects synapse function in the brain. However, these diseases alter synapses through different mechanisms, ultimately resulting in altered synaptic transmission and/or plasticity. Glutamate is the major neurotransmitter that mediates excitatory synaptic transmission in the brain through activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors. These receptors have therefore been identified as a target for the development of therapeutic treatments for neurological disorders including epilepsy, neurodegenerative diseases, autism, and drug addiction. The fact that AMPA receptors play a dominant role throughout the brain raises the significant challenge of selectively targeting only those regions affected by disease, and clinical trials have raised doubt regarding the feasibility of specifically targeting AMPA receptors for new therapeutic options. Benzamide compounds that act as positive allosteric AMPA receptor modulators, known as AMPAkines, can act on specific brain regions and were initially proposed to revolutionize the treatment of cognitive deficits associated with neurological disorders. Their therapeutic potential has since declined due to inconsistent results in clinical trials. However, recent advances in basic biomedical research are significantly increasing our knowledge of AMPA receptor structure, binding sites, and interactions with auxiliary proteins. In particular, the large complex of postsynaptic proteins that interact with AMPA receptor subunits have been shown to control AMPA receptor insertion, location, pharmacology, synaptic transmission, and plasticity. These proteins are now being considered as alternative therapeutic target sites for modulating AMPA receptors in neurological disorders.
authors.affiliation: Department of Physiology, Centre for Brain Research, University of Auckland, Auckland, New Zealand.
authors.forename: Kevin
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Physiology, Centre for Brain Research, University of Auckland, Auckland, New Zealand.
authors.forename: Lucy
authors.initials: L
authors.lastname: Goodman
authors.affiliation: Department of Physiology, Centre for Brain Research, University of Auckland, Auckland, New Zealand.
authors.forename: Chantelle
authors.initials: C
authors.lastname: Fourie
authors.affiliation: School of Psychology, Victoria University, Wellington, New Zealand.
authors.forename: Susan
authors.initials: S
authors.lastname: Schenk
authors.affiliation: Department of Anatomy, University of Otago, Dunedin, New Zealand.
authors.forename: Beulah
authors.initials: B
authors.lastname: Leitch
authors.affiliation: Department of Physiology, Centre for Brain Research, University of Auckland, Auckland, New Zealand. Electronic address: jm.montgomery@auckland.ac.nz.
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Montgomery
mesh_terms: D001549:Benzamides / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004827:Epilepsy / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D058990:Molecular Targeted Therapy; D009422:Nervous System Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D009473:Neuronal Plasticity / Q000235:genetics; D018091:Receptors, AMPA / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D001549:Benzamides; D018091:Receptors, AMPA; C037689:benzamide
keywords: AMPA receptor; Autism; Drug addiction; Epilepsy; Glutamate; MAGUKs; Neurodegenerative disease; Postsynaptic density; Shanks