The NMDA receptor as a target for cognitive enhancement

Collingridge, Graham L.; Volianskis, Arturas; Bannister, Neil; Hanna, Lydia; Mercier, Marion; Tidball, Patrick; Fang, Guangyu; Irvine, Mark W.; Costa, Blaise M.; Monaghan, Daniel T.; Bortolotto, Zuner A.; Molnár, Elek; Lodge, David; Jane, David E.

doi:10.1016/j.neuropharm.2012.06.051

Cited by 211 publications

(172 citation statements)

References 195 publications

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“…The majority of NMDARs in the central nervous systems are heteromeric complexes formed by two GluN1 and two GluN2 subunits (Ulbrich and Isacoff, 2007), of which there are four subtypes (GluN2A-D) with temporal and spatial variation in expression (Watanabe et al, 1992;Ishii et al, 1993;Monyer et al, 1994). The development of GluN2-selective modulators provides a therapeutic opportunity to target NMDAR subtypes with anatomically restricted expression patterns, thereby minimizing potential side effects (Kalia et al, 2008;Ogden and Traynelis, 2011;Collingridge et al, 2013). Subunitselective allosteric modulators exist for the GluN2A (TCN-201), GluN2B (ifenprodil), and GluN2C/GluN2D subunits (6,7-dimethoxy-1-[(4-methoxyphenoxy)methyl]-3,4-dihydroisoquinolin-2(1H)-yl)methanone], QNZ, UBP, DQP analogs) (Williams et al, 1993;Bettini et al, 2010;Mullasseril et al, 2010;Acker et al, 2011;Hansen and Traynelis, 2011;Costa et al, 2012;Hansen et al, 2012;Monaghan et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Structural Determinants and Mechanism of Action of a GluN2C-selective NMDA Receptor Positive Allosteric Modulator

et al. 2014

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NMDA receptors are tetrameric complexes of GluN1, GluN2A-D, and GluN3A-B subunits and are involved in normal brain function and neurologic disorders. We identified a novel class of stereoselective pyrrolidinone (PYD) positive allosteric modulators for GluN2C-containing NMDA receptors, exemplified by methyl 4-(3-acetyl-4-hydroxy-1-[2-(2-methyl-1H-indol-3-yl)ethyl]-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate. Here we explore the site and mechanism of action of a prototypical analog, PYD-106, which at 30 mM does not alter responses of NMDA receptors containing GluN2A, GluN2B, and GluN2D and has no effect on AMPA [a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid] and kainate receptors. Coapplication of 50 mM PYD-106 with a maximally effective concentration of glutamate and glycine increases the response of GluN1/GluN2C NMDA receptors in HEK-293 cells to 221% of that obtained in the absence of PYD (taken as 100%). Evaluation of the concentration dependence of this enhancement revealed an EC 50 value for PYD of 13 mM. PYD-106 increased opening frequency and open time of single channel currents activated by maximally effective concentrations of agonist but only had modest effects on glutamate and glycine EC 50 . PYD-106 selectively enhanced the responses of diheteromeric GluN1/GluN2C receptors but not triheteromeric GluN1/GluN2A/GluN2C receptors. Inclusion of residues encoded by GluN1-exon 5 attenuated the effects of PYD. Three GluN2C residues (Arg194, Ser470, Lys470), at which mutagenesis virtually eliminated PYD function, line a cavity at the interface of the ligand binding and the amino terminal domains in a homology model of GluN1/GluN2C built from crystallographic data on GluN1/GluN2B. We propose that this domain interface constitutes a new allosteric modulatory site on the NMDA receptor.

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Section: Introductionmentioning

confidence: 99%

Structural Determinants and Mechanism of Action of a GluN2C-selective NMDA Receptor Positive Allosteric Modulator

et al. 2014

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“…N-Methyl D-aspartate-type glutamate receptors (NMDARs) play an important role in hippocampal LTP and LTD, and are essential for learning and memory (Morris et al 1986;Bliss and Collingridge 1993;Bear 1996;Milner et al 1998;Martin et al 2000;Neves et al 2008). Because of the vital role of NMDARs in some forms of memory, regulation of NMDAR function is a potential strategy for preventing or reversing cognitive decline in the aging population (Collingridge et al 2013).…”

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confidence: 99%

MHC class I immune proteins are critical for hippocampus-dependent memory and gate NMDAR-dependent hippocampal long-term depression

et al. 2013

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Memory impairment is a common feature of conditions that involve changes in inflammatory signaling in the brain, including traumatic brain injury, infection, neurodegenerative disorders, and normal aging. However, the causal importance of inflammatory mediators in cognitive impairments in these conditions remains unclear. Here we show that specific immune proteins, members of the major histocompatibility complex class I (MHC class I), are essential for normal hippocampus-dependent memory, and are specifically required for NMDAR-dependent forms of long-term depression (LTD) in the healthy adult hippocampus. In b2m 2/2 TAP 2/2 mice, which lack stable cell-surface expression of most MHC class I proteins, NMDAR-dependent LTD in area CA1 of adult hippocampus is abolished, while NMDAR-independent forms of potentiation, facilitation, and depression are unaffected. Altered NMDAR-dependent synaptic plasticity in the hippocampus of b2m 2/2 TAP 2/2 mice is accompanied by pervasive deficits in hippocampus-dependent memory, including contextual fear memory, object recognition memory, and social recognition memory. Thus normal MHC class I expression is essential for NMDAR-dependent hippocampal synaptic depression and hippocampus-dependent memory. These results suggest that changes in MHC class I expression could be an unexpected cause of disrupted synaptic plasticity and cognitive deficits in the aging, damaged, and diseased brain.

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“…For this work, PF-4778574 efficacy was conceptually rooted in AMPAR potentiation overcoming certain cognitive impairments in schizophrenia (Millan et al, 2012;Moghaddam and Javitt, 2012;Collingridge et al, 2013). This rationale stems from the hypothesis that schizophrenia fundamentally results from dysfunction in N-methyl-D-aspartate receptor (NMDAR) glutamatergic neurotransmission (Olney and Farber, 1995;Goff and Coyle, 2001;Javitt, 2007).…”

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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The NMDA receptor as a target for cognitive enhancement

Cited by 211 publications

References 195 publications

Structural Determinants and Mechanism of Action of a GluN2C-selective NMDA Receptor Positive Allosteric Modulator

Structural Determinants and Mechanism of Action of a GluN2C-selective NMDA Receptor Positive Allosteric Modulator

MHC class I immune proteins are critical for hippocampus-dependent memory and gate NMDAR-dependent hippocampal long-term depression

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

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