Positive AMPA receptor modulation in the treatment of neuropsychiatric disorders: A long and winding road |
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| Affiliation: | 1. Experimental Therapeutics & Pathophysiology Branch, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA;2. School of Medicine and Surgery, University of Milano-Bicocca, Italy;3. Division of Medical Sciences, University of Victoria, Victoria, BC, Canada;4. Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Italy |
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| Abstract: | Glutamatergic transmission is widely implicated in neuropsychiatric disorders, and the discovery that ketamine elicits rapid-acting antidepressant effects by modulating α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) signaling has spurred a resurgence of interest in the field. This review explores agents in various stages of development for neuropsychiatric disorders that positively modulate AMPARs, both directly and indirectly. Despite promising preclinical research, few direct and indirect AMPAR positive modulators have progressed past early clinical development. Challenges such as low potency have created barriers to effective implementation. Nevertheless, the functional complexity of AMPARs sets them apart from other drug targets and allows for specificity in drug discovery. Additional effective treatments for neuropsychiatric disorders that work through positive AMPAR modulation may eventually be developed. |
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| Keywords: | Glutamatergic modulators AMPA Ampakines mGluR modulators Ketamine Depression ADHD" },{" #name" :" keyword" ," $" :{" id" :" k0040" }," $$" :[{" #name" :" text" ," _" :" attention deficit hyperactivity disorder AMPA" },{" #name" :" keyword" ," $" :{" id" :" k0050" }," $$" :[{" #name" :" text" ," _" :" α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid AMPAR" },{" #name" :" keyword" ," $" :{" id" :" k0060" }," $$" :[{" #name" :" text" ," _" :" AMPA receptor BDNF" },{" #name" :" keyword" ," $" :{" id" :" k0070" }," $$" :[{" #name" :" text" ," _" :" brain-derived neurotrophic factor GABA" },{" #name" :" keyword" ," $" :{" id" :" k0080" }," $$" :[{" #name" :" text" ," _" :" gamma aminobutyric acid HNK" },{" #name" :" keyword" ," $" :{" id" :" k0090" }," $$" :[{" #name" :" text" ," _" :" hydroxynorketamine MCI" },{" #name" :" keyword" ," $" :{" id" :" k0100" }," $$" :[{" #name" :" text" ," _" :" mild cognitive impairment MDD" },{" #name" :" keyword" ," $" :{" id" :" k0110" }," $$" :[{" #name" :" text" ," _" :" major depressive disorder mTORC" },{" #name" :" keyword" ," $" :{" id" :" k0120" }," $$" :[{" #name" :" text" ," _" :" mammalian target of rapamycin complex NGF" },{" #name" :" keyword" ," $" :{" id" :" k0130" }," $$" :[{" #name" :" text" ," _" :" nerve growth factor NMDAR" },{" #name" :" keyword" ," $" :{" id" :" k0140" }," $$" :[{" #name" :" text" ," _" :" noncompetitive allosteric N-methyl-D-aspartate receptor PAM" },{" #name" :" keyword" ," $" :{" id" :" k0150" }," $$" :[{" #name" :" text" ," _" :" positive allosteric modulator |
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