Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Dec;26(12):2816-2838.
doi: 10.1016/j.drudis.2021.07.027. Epub 2021 Aug 3.

Positive AMPA receptor modulation in the treatment of neuropsychiatric disorders: A long and winding road

Bashkim Kadriu  1 , Laura Musazzi  2 , Jenessa N Johnston  3 , Lisa E Kalynchuk  4 , Hector J Caruncho  4 , Maurizio Popoli  5 , Carlos A Zarate Jr  6
Affiliations
Review

Positive AMPA receptor modulation in the treatment of neuropsychiatric disorders: A long and winding road

Bashkim Kadriu et al. Drug Discov Today. 2021 Dec.

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.

Keywords: AMPA; Ampakines; Depression; Glutamatergic modulators; Ketamine; mGluR modulators.

PubMed Disclaimer

Conflict of interest statement

Conflicts of interest

Dr Zarate is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation; as a co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydroxylated and hydroxylated metabolites of (R,S)-ketamine in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. He has assigned his patent rights to the United States Government but will share a percentage of any royalties that may be received by the Government. Dr Kadriu is now a full-time employee at Janssen Research & Development, LLC and owns stock and stock options in Johnson & Johnson; this work was completed while he was a full-time employee of the NIMH. Dr Musazzi is a consultant and has received speaker fees from Janssen Italy. Dr Popoli has received research contracts from Rodin Therapeutics (now Alkermes) in the last 36 months and received research contracts from Merck, GlaxoSmithKline, Servier, Sigma-Tau, Fidia, and Abbott. All other authors have no conflict of interest to disclose, financial or otherwise.

Figures

FIGURE 1
FIGURE 1
Molecular structure of AMPAkines and other α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) positive allosteric modulators (PAMs).
See this image and copyright information in PMC

References

    1. Alt A, Nisenbaum ES, Bleakman D, Witkin JM. A role for AMPA receptors in mood disorders. Biochem Pharmacol 2006; 71: 1273–88. - PubMed
    1. Nisenbaum ES, Witkin JM, Positive allosteric modulation of AMPA receptors: a novel potential antidepressant therapy, in: Skolnick P (Ed.), Glutamate-based therapies for psychiatric disorders – Milestones in drug therapy, Birkäuser, Basel, 2010, pp. 39–56.
    1. Skolnick P Glutamate-based therapies for psychiatric disorders – Milestones in drug therapy, Basel: Birkäuser; 2010.
    1. Kishimoto T, Chawla JM, Hagi K, Zarate CA, Kane JM, Bauer M, Correll CU, Single-dose infusion ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories, Psychol Med 46 (2016) 1459–1472. - PMC - PubMed
    1. Yang C, Shirayama Y, Zhang JC, Ren Q, Yao W, Ma M, et al. R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects. Transl Psychiatry 2015; 5: e632. - PMC - PubMed

Publication types