Therapeutic potential of positive AMPA modulators and their relationship to AMPA receptor subunits. A review of preclinical data

  title={Therapeutic potential of positive AMPA modulators and their relationship to AMPA receptor subunits. A review of preclinical data},
  author={Mark D. Black},
  • M. Black
  • Published 26 January 2005
  • Biology, Psychology
  • Psychopharmacology
BackgroundPositive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) modulators enhance glutamate transmission via the AMPA receptor by altering the rate of desensitization; alone they have no intrinsic activity. They are the only class of compounds known that may pharmacologically separate AMPA subtypes.ObjectiveThis manuscript will review preclinical work on positive AMPA modulators, with clinical examples where relevant.ResultsThe activity of these compounds appears to be… 

Are AMPA Receptor Positive Allosteric Modulators Potential Pharmacotherapeutics for Addiction?

This preclinical literature is reviewed, novel data collected in the laboratory is discussed, and future research directions for the possible development of AMPA PAMs as anti-addiction medications are recommended.

Therapeutic Potential of Positive AMPA Receptor Modulators in the Treatment of Neuropsychiatric Disorders

Animal studies characterising the pharmacological and behavioural effects of these substances have provided the rationale for several initial attempts to use these drugs in neuropsychiatric clinical settings, and applications in schizophrenia, Alzheimer’s disease and mild cognitive impairment have been initiated.

Pharmacological characterisation of MDI-222, a novel AMPA receptor positive allosteric modulator with an improved safety profile

It is demonstrated that MDI-222 is an AMPAR PAM, since it enhanced AMPAR function in vitro at human and rat homomeric receptors, and potentiated hetero-oligomeric AMPARs in rat neurons.

Auxiliary Proteins are the Predominant Determinants of Differential Efficacy of Clinical Candidates Acting as AMPA Receptor Positive Allosteric Modulators

It is concluded that compounds that discriminate between AMPARs complexed with distinct TARPs, and particularly those with lower stargazin/γ2 efficacy such as BIIB104, could act as viable procognitive therapeutics.

Positive Allosteric Modulation of AMPAR by PF-4778574 Produced Rapid Onset Antidepressant Actions in Mice.

It is found that postsynaptic AMPAR activation followed by activation of L-VDCC and subsequent VGF/BDNF/TrkB/AKT signaling are required for the rapid antidepressant effects of PF-4778574, and a promising therapeutic profile is found for this novel AMPAR positive allosteric agonist.

Pharmacological characterisation of S 47445, a novel positive allosteric modulator of AMPA receptors

Results indicate that S 47445 is a potent and selective AMPA-PAM presenting procognitive and potential neuroprotective properties and does not demonstrate neurotoxic effect against glutamate-mediated excitotoxicity in vitro.

AMPA receptor potentiators : mechanisms of neuroplasticity

BDNF is identified as one key mediator of the neurotrophic effects of AMPA receptor potentiation, suggesting that LY404187 increases neurite length in vitro by a BDNF mediated mechanism.



Neurotrophic actions of the novel AMPA receptor potentiator, LY404187, in rodent models of Parkinson's disease.

LY404187: a novel positive allosteric modulator of AMPA receptors.

The data suggest that AMPA receptor potentiators may be therapeutically beneficial for treating cognitive deficits in a variety of disorders, particularly those that are associated with reduced glutamatergic signaling such as schizophrenia.

Effect of AMPA receptor modulators on hippocampal and cortical function.

AMPA receptor agonists, antagonists and modulators: their potential for clinical utility

From the understanding of neuronal circuitry and its involvement in brain function, agonists and positive allosteric modulators are predicted to improve the negative symptomatology in schizophrenia, and to improve memory, behavioural and cognition skills in dementias associated with neurodegenerative disorders or trauma.

NMDA receptor pharmacology: perspectives from molecular biology.

NMDA receptor subtype selective drugs can be created, and further understanding of subtype specific mechanisms ultimately may allow successful use of NMDA receptor antagonists as therapeutic agents.

AMPA receptor modulators as cognitive enhancers.

  • G. Lynch
  • Biology, Psychology
    Current opinion in pharmacology
  • 2004

A molecular determinant for submillisecond desensitization in glutamate receptors.

These findings suggest that rapid desensitization of AMPA receptors can be regulated by the expression and alternative splicing of GluR-D gene transcripts.

The NMDA receptor NR2B subunit: a valid therapeutic target for multiple CNS pathologies.

  • P. Chazot
  • Biology
    Current medicinal chemistry
  • 2004
The NMDAR2B subunit is the focus of increasing interest as a therapeutic target in a wide range of CNS pathologies, including acute and chronic pain, stroke and head trauma, drug-induced dyskinesias, and dementias and the benefit of a structural template for the ifenprodil binding site should further improve future structure activity relationships.