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Positive Allosteric Modulation of AMPA Receptors: A Novel Potential Antidepressant Therapy

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Glutamate-based Therapies for Psychiatric Disorders

Part of the book series: Milestones in Drug Therapy ((MDT))

Abstract

This review focuses on positive allosteric modulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors as a novel mechanism to impact mood in the therapy of major depressive disorder (MDD). Several classes of positive allosteric modulators (AMPA receptor potentiators or AMPAkines) have been discovered. Structural and functional studies have demonstrated that different types of positive allosteric modulators have distinct but overlapping binding domains with the extracellular portion of the receptor. Such differences in turn confer unique biophysical mechanisms of allosteric modulation of AMPA receptor function. More recent findings indicate that auxiliary proteins associated with AMPA receptors can further influence the manner in which potentiators ultimately modulate channel function. Support for the hypothesis that AMPA receptor potentiation may be beneficial in MDD comes from both preclinical and clinical findings. Multiple standards of care used to treat MDD have been shown to enhance surface expression of AMPA receptor subunits, increase AMPA subunit phosphorylation, and/or amplify AMPA channel conductance. In addition, AMPA receptor potentiators can enhance brain levels of brain-derived neurotrophic factor, which has been implicated in neuroplasticity and linked to improvements in depression scores after antidepressant treatment. Indeed, neurogenesis has been demonstrated after the application of AMPA receptor potentiators both in vitro and in vivo. Finally, positive allosteric modulators of AMPA receptors are active in a number of rodent models predictive of antidepressant efficacy and where tested, these effects have been prevented by blockade of AMPA receptors. Taken together, biochemical, behavioral, and clinical data suggest that AMPA receptor potentiators may provide a novel therapeutic approach to MDD.

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Abbreviations

AMPA:

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

BDNF:

Brain-derived neurotrophic factor

cAMP:

Adenosine 3′,5′-cyclic monophosphate

CNQX:

6-cyano-7-nitroquinoxaline-2,3-dione

CX516:

Piperidine, 1-(6-quinoxalinylcarbonyl)- (9CI); Ampalex; BDP 12

CX691:

Piperidine, 1-(2,1,3-benzoxadiazol-5-ylcarbonyl)- (9CI), Farampator

DARPP-32:

Dopamine- and cAMP-regulated phosphoprotein of M r 32,000

DNQX:

6,7-dinitroquinoxaline-2,3-dione

GPCR:

G protein-coupled receptor

GYKI:

53655: 7H-1,3-Dioxolo[4,5-h][2,3]benzodiazepine-7-carboxamide, 5-(4-aminophenyl)-8,9-dihydro-N,8-dimethyl-, monohydrochloride (9CI)

LY392098:

N-2-(4-(3-Thienyl)phenyl)propyl 2-propanesulfonamide

LY404187:

N-2-(4-(4-Cyanophenyl)phenyl)propyl 2-propanesulfonamide

LY451646:

N-[2-(4′-cyano[1,1′-biphenyl]-4-yl)propyl]- (9CI)

LY503430:

4′-[(1R)-1-fluoro-1-methyl-2-[[(1-methylethyl)sulfonyl]amino]ethyl]-N-methyl- (9CI)

MGS0039:

2-amino-3-[(3,4-dichlorophenyl)methoxy]-6-fluoro-, (1R,2R,3R,5R,6R)- (9CI)

NMDA:

N-methyl-D-aspartate

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Acknowledgments

We are also grateful to our many colleagues for discussion in particular to Drs. Phil Skolnick, Darryle Schoepp, James Monn, Paul Ornstein, Eleni Tzavara, David Bleakman, and David Bredt.

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  1. Neuroscience Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA

    Eric S. Nisenbaum

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Correspondence to Eric S. Nisenbaum .

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  1. Div Pharmacotherapies & Medical Conseque, National Institute on Drug Abuse, Executive Boulevard 6001, Rockville, 20852, Maryland, USA

    Phil Skolnick

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Nisenbaum, E.S., Witkin, J.M. (2010). Positive Allosteric Modulation of AMPA Receptors: A Novel Potential Antidepressant Therapy. In: Skolnick, P. (eds) Glutamate-based Therapies for Psychiatric Disorders. Milestones in Drug Therapy. Birkhäuser, Basel. https://doi.org/10.1007/978-3-0346-0241-9_3

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