Positive Allosteric Modulators of the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor

Grove, Simon J. A.; Jamieson, Craig; Maclean, John; Morrow, John A.; Rankovic, Zoran

doi:10.1021/jm1000419

Cited by 37 publications

(22 citation statements)

References 43 publications

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“…From the figure, it is clear that there is no particular effect on 40 Hz activity—within a reasonable range of parameter assumptions, a virtual ampakine that effectively normalized 40 Hz resonance would create supraphysiologic levels of 30 and 20 Hz activity. This is consistent with clinical findings: On theoretical grounds, it was felt that this class of drugs may have an ameliorative effects on schizophrenia and, a number of ampakines have been developed for clinical use (CX516 [Ampalex], CX717, CX691/Org24448 [Faramptor], and LY451395) [75]. However, clinical trials [76] have not borne out their effectiveness in patient populations.…”

Section: Resultssupporting

confidence: 62%

Development of Antipsychotic Medications with Novel Mechanisms of Action Based on Computational Modeling of Hippocampal Neuropathology

Siekmeier

vanMaanen

2013

PLoS ONE

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A large number of cellular level abnormalities have been identified in the hippocampus of schizophrenic subjects. Nonetheless, it remains uncertain how these pathologies interact at a system level to create clinical symptoms, and this has hindered the development of more effective antipsychotic medications. Using a 72-processor supercomputer, we created a tissue level hippocampal simulation, featuring multicompartmental neuron models with multiple ion channel subtypes and synaptic channels with realistic temporal dynamics. As an index of the schizophrenic phenotype, we used the specific inability of the model to attune to 40 Hz (gamma band) stimulation, a well-characterized abnormality in schizophrenia. We examined several possible combinations of putatively schizophrenogenic cellular lesions by systematically varying model parameters representing NMDA channel function, dendritic spine density, and GABA system integrity, conducting 910 trials in total. Two discrete “clusters” of neuropathological changes were identified. The most robust was characterized by co-occurring modest reductions in NMDA system function (-30%) and dendritic spine density (-30%). Another set of lesions had greater NMDA hypofunction along with low level GABA system dysregulation. To the schizophrenic model, we applied the effects of 1,500 virtual medications, which were implemented by varying five model parameters, independently, in a graded manner; the effects of known drugs were also applied. The simulation accurately distinguished agents that are known to lack clinical efficacy, and identified novel mechanisms (e.g., decrease in AMPA conductance decay time constant, increase in projection strength of calretinin-positive interneurons) and combinations of mechanisms that could re-equilibrate model behavior. These findings shed light on the mechanistic links between schizophrenic neuropathology and the gamma band oscillatory abnormalities observed in the illness. As such, they generate specific falsifiable hypotheses, which can guide postmortem and other laboratory research. Significantly, this work also suggests specific non-obvious targets for potential pharmacologic agents.

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Section: Resultssupporting

confidence: 62%

Development of Antipsychotic Medications with Novel Mechanisms of Action Based on Computational Modeling of Hippocampal Neuropathology

Siekmeier

vanMaanen

2013

PLoS ONE

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“…Consequently, AMPAR modulation has been targeted to treat numerous psychiatric and neurological diseases (O'Neill et al, 2004;Zarate and Manji, 2008). AMPARcentric drug discovery (Black, 2005;Grove et al, 2010) has primarily focused on receptor activation via positive allosteric modulators (i.e., "potentiators") that tend to better match the degree and/or duration of AMPAR opening to synaptic activity than orthosteric agonists. Nonetheless, excessive AMPAR stimulation can cause degeneration of Purkinje cells and hippocampal neurons (Garthwaite and Garthwaite, 1991) and/or convulsion (Yamada, 1998).…”

mentioning

confidence: 99%

Positive Allosteric Modulation of AMPA Receptors from Efficacy to Toxicity: The Interspecies Exposure-Response Continuum of the Novel Potentiator PF-4778574

Shaffer

Hurst

Scialis

et al. 2013

J Pharmacol Exp Ther

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a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) positive allosteric modulation (i.e., "potentiation") has been proposed to overcome cognitive impairments in schizophrenia, but AMPAR overstimulation can be excitotoxic. Thus, it is critical to define carefully a potentiator's mechanismbased therapeutic index (TI) and to determine confidently its translatability from rodents to higher-order species. Accordingly, the novel AMPAR potentiator N-{(3R,4S)-3-[4-(5-cyano-2-thienyl) phenyl]tetrahydro-2H-pyran-4-yl}propane-2-sulfonamide (PF-4778574) was characterized in a series of in vitro assays and single-dose animal studies evaluating AMPAR-mediated activities related to cognition and safety to afford an unbound brain compound concentration (C b,u )-normalized interspecies exposure-response relationship. Because it is unknown which AMPAR subtype(s) may be selectively potentiated for an optimal TI, PF-4778574 binding affinity and functional potency were determined in rodent tissues expected to express a native mixture of AMPAR subunits and their associated proteins to afford composite pharmacological values. Functional activity was also quantified in recombinant cell lines stably expressing human GluA2 flip or flop homotetramers. Procognitive effects of PF-4778574 were evaluated in both rat electrophysiological and nonhuman primate (nhp) behavioral models of pharmacologically induced N-methyl-D-aspartate receptor hypofunction. Safety studies assessed cerebellum-based AMPAR activation (mouse) and motor coordination disruptions (mouse, dog, and nhp), as well as convulsion (mouse, rat, and dog). The resulting empirically derived exposure-response continuum for PF-4778574 defines a single-dose-based TI of 8-to 16-fold for self-limiting tremor, a readily monitorable clinical adverse event. Importantly, the C b,u mediating each physiological effect were highly consistent across species, with efficacy and convulsion occurring at just fractions of the in vitro-derived pharmacological values.

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“…A number of review articles have been published which summarize the general area of medicinal chemistry directed toward AMPAfuture science group Review Ward, Pennicott & Beswick positive modulators [24][25][111][112] or focus on specific templates. The reviews are complemented by several focused articles describing specific medicinal chemistry approaches or detailed profiles of advanced compounds.…”

Section: Summary Of Recent Journal Developments: Focus On New Chemotypesmentioning

confidence: 99%

AMPA Receptor-Positive Allosteric Modulators for the Treatment of Schizophrenia: An Overview of Recent Patent Applications

2015

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The role of glutamate and its receptors in central nervous system biology and disease has long been of interest to scientists involved in both fundamental research and drug discovery, however the complex pharmacology and lack of highly selective compounds has severely hampered drug discovery efforts in this area. Recent advances in the identification and profiling of positive allosteric modulators of the AMPA receptor offer a potential way forward and the hope of a new treatment for schizophrenia. This article will review recent patent applications published in this area.

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Positive Allosteric Modulators of the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor

Cited by 37 publications

References 43 publications

Development of Antipsychotic Medications with Novel Mechanisms of Action Based on Computational Modeling of Hippocampal Neuropathology

Development of Antipsychotic Medications with Novel Mechanisms of Action Based on Computational Modeling of Hippocampal Neuropathology

Positive Allosteric Modulation of AMPA Receptors from Efficacy to Toxicity: The Interspecies Exposure-Response Continuum of the Novel Potentiator PF-4778574

AMPA Receptor-Positive Allosteric Modulators for the Treatment of Schizophrenia: An Overview of Recent Patent Applications

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