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• W2289682110 abstract "In this issue of Neuron, Hackos et al., 2016Hackos D.H. Lupardus P.J. Grand T. Chen Y. Wang T.-M. Reynen P. Gustafson A. Wallweber H.J.A. Volgraf M. Sellers B.D. et al.Neuron. 2016; 89 (this issue): 983-999Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar report the discovery of novel positive allosteric modulators that are highly selective for GluN2A-containing NMDA receptors. This novel class of PAMs shows distinct effects on synaptic plasticity. In this issue of Neuron, Hackos et al., 2016Hackos D.H. Lupardus P.J. Grand T. Chen Y. Wang T.-M. Reynen P. Gustafson A. Wallweber H.J.A. Volgraf M. Sellers B.D. et al.Neuron. 2016; 89 (this issue): 983-999Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar report the discovery of novel positive allosteric modulators that are highly selective for GluN2A-containing NMDA receptors. This novel class of PAMs shows distinct effects on synaptic plasticity. The NMDA receptor (NMDAR) is a ligand- and voltage-gated ionotropic glutamate receptor that is critically involved in multiple forms of synaptic plasticity that are believed to provide the cellular basis for learning and memory. Dysfunction of NMDAR signaling has been implicated in a variety of psychiatric and neurological disorders and has drawn tremendous interest as a potential drug target. In addition to severe pathological consequences of excessive NMDAR activation, multiple studies suggest that hypofunction of NMDARs may contribute to the pathophysiology of schizophrenia and other disorders that include impaired cognitive function (Balu and Coyle, 2015Balu D.T. Coyle J.T. Curr. Opin. Pharmacol. 2015; 20: 109-115Crossref Scopus (147) Google Scholar). Thus, pharmacologically increasing NMDAR activity might provide a therapeutic benefit for these disorders. Unfortunately, agents that directly activate NMDARs induce severe toxicity, including seizures and neuronal death. Based on this, the major focus has been on developing pharmacological agents that do not act directly on NMDARs but indirectly increase NMDAR function and may avoid the inherent toxicity associated with excessive activation of NMDARs. For instance, selective inhibitors of the glycine transporter, GlyT1, or of the serine metabolizing enzyme, D-amino acid oxidase, increase NMDAR signaling by increasing synaptic levels of the NMDAR coagonists glycine and serine, respectively (Balu and Coyle, 2015Balu D.T. Coyle J.T. Curr. Opin. Pharmacol. 2015; 20: 109-115Crossref Scopus (147) Google Scholar). Also, selective positive allosteric modulators (PAMs) of the mGlu5 subtype of metabotropic glutamate receptor indirectly enhance NMDAR signaling by targeting a G protein-coupled glutamate receptor that regulates NMDAR function (Conn et al., 2014Conn P.J. Lindsley C.W. Meiler J. Niswender C.M. Nat. Rev. Drug Discov. 2014; 13: 692-708Crossref PubMed Scopus (212) Google Scholar). While efforts to increase NMDAR signaling without directly targeting the NMDAR protein show promise, each has encountered challenges. For instance, clinical studies failed to establish efficacy of GlyT1 inhibitors in schizophrenia patients (Balu and Coyle, 2015Balu D.T. Coyle J.T. Curr. Opin. Pharmacol. 2015; 20: 109-115Crossref Scopus (147) Google Scholar), leading to the suggestion that GlyT1 may not regulate synaptic levels of the NMDAR coagonist at specific synapses that are important for schizophrenia. The mGlu5 PAMs have robust efficacy in multiple animal models, but some mGlu5 PAMs induce seizures and excitotoxic cell death, and these effects are likely to be in part mediated by excessive potentiation of NMDAR currents in limbic and forebrain regions (Rook et al., 2015Rook J.M. Xiang Z. Lv X. Ghoshal A. Dickerson J.W. Bridges T.M. Johnson K.A. Foster D.J. Gregory K.J. Vinson P.N. et al.Neuron. 2015; 86: 1029-1040Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). Interestingly, novel mGlu5 PAMs have been developed that do not enhance NMDAR currents but retain efficacy in some animal models without observable neurotoxic effects (Rook et al., 2015Rook J.M. Xiang Z. Lv X. Ghoshal A. Dickerson J.W. Bridges T.M. Johnson K.A. Foster D.J. Gregory K.J. Vinson P.N. et al.Neuron. 2015; 86: 1029-1040Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). However, this strategy will not be effective in achieving efficacy that requires increases in NMDAR signaling. Previous indirect approaches have been based on the assumption that directly targeting NMDARs will inevitably lead to neurotoxicity. However, NMDARs are heterotetrameric receptors comprised of different combinations of 2 GluN1 subunits and 2 GluN2 subunits; and GluN2 subunits are encoded by 4 different gene products (GluN2A–D). NMDARs with different subunit compositions can have fundamentally different biophysical and synaptic properties and distinct cellular and subcellular localizations (Strong et al., 2014Strong K.L. Jing Y. Prosser A.R. Traynelis S.F. Liotta D.C. Expert Opin. Ther. Pat. 2014; 24: 1349-1366Crossref Scopus (30) Google Scholar). Recent years have seen major advances in discovery of highly selective negative allosteric modulators (NAMs) of NMDARs that contain specific subunits, including selective GluN2B (Menniti et al., 1997Menniti F. Chenard B. Collins M. Ducat M. Shalaby I. White F. Eur. J. Pharmacol. 1997; 331: 117-126Crossref PubMed Scopus (100) Google Scholar, Williams, 1993Williams K. Mol. Pharmacol. 1993; 44: 851-859PubMed Google Scholar, Yue et al., 2015Yue M. Hinkle K.M. Davies P. Trushina E. Fiesel F.C. Christenson T.A. Schroeder A.S. Zhang L. Bowles E. Behrouz B. et al.Neurobiol. Dis. 2015; 78: 172-195Crossref PubMed Scopus (150) Google Scholar) and GluN2C/2D (Zhu and Paoletti, 2015Zhu S. Paoletti P. Curr. Opin. Pharmacol. 2015; 20: 14-23Crossref PubMed Scopus (113) Google Scholar). Investigators interested in increasing NMDAR signaling are now taking the first steps toward developing highly selective PAMs of NMDARs with defined subunit compositions (Jambrina et al., 2016Jambrina E. Cerne R. Smith E. Scampavia L. Cuadrado M. Findlay J. Krambis M.J. Wakulchik M. Chase P. Brunavs M. et al.J. Biomol. Screen. 2016; (Published online February 2, 2016. 1087057116628437)Google Scholar, Khatri et al., 2014Khatri A. Burger P.B. Swanger S.A. Hansen K.B. Zimmerman S. Karakas E. Liotta D.C. Furukawa H. Snyder J.P. Traynelis S.F. Mol. Pharmacol. 2014; 86: 548-560Crossref PubMed Scopus (55) Google Scholar, Santangelo Freel et al., 2013Santangelo Freel R.M. Ogden K.K. Strong K.L. Khatri A. Chepiga K.M. Jensen H.S. Traynelis S.F. Liotta D.C. J. Med. Chem. 2013; 56: 5351-5381Crossref Scopus (42) Google Scholar, Zimmerman et al., 2014Zimmerman S.S. Khatri A. Garnier-Amblard E.C. Mullasseril P. Kurtkaya N.L. Gyoneva S. Hansen K.B. Traynelis S.F. Liotta D.C. J. Med. Chem. 2014; 57: 2334-2356Crossref Scopus (41) Google Scholar). This approach has been highly successful in selectively increasing activity of other ligand-gated ion channels (Taly et al., 2014Taly A. Hénin J. Changeux J.P. Cecchini M. Channels (Austin). 2014; 8: 350-360Crossref Scopus (27) Google Scholar) and G protein-coupled receptors (GPCRs) (Conn et al., 2014Conn P.J. Lindsley C.W. Meiler J. Niswender C.M. Nat. Rev. Drug Discov. 2014; 13: 692-708Crossref PubMed Scopus (212) Google Scholar). It is hoped that NMDAR subunit-selective PAMs will minimize risks associated with excessive activation of NMDARs by maintaining spatial and temporal patterns of NMDAR signaling and achieving high subunit selectivity by targeting allosteric sites, which are less highly conserved than the orthosteric glutamate binding site. In this issue of Neuron, Hackos et al., 2016Hackos D.H. Lupardus P.J. Grand T. Chen Y. Wang T.-M. Reynen P. Gustafson A. Wallweber H.J.A. Volgraf M. Sellers B.D. et al.Neuron. 2016; 89 (this issue): 983-999Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar report discovery and characterization of a novel class of highly selective PAMs for NMDARs containing the GluN2A subunit. A high-throughput screen and subsequent medicinal chemistry efforts led to discovery of a panel of structurally related compounds that induce a concentration-dependent potentiation of glutamate (Glu)-induced responses in a cell line expressing GluN2A-containing NMDARs with high selectivity for GluN2A relative to GluN2B, GluN2C, or GluN2D. In addition to effects on diheteromeric GluN1/GluN2A NMDARs, GNE-6901 and GNE-8324 also potentiated responses in a cell line expressing triheteromeric GluN1/GluN2A/GluN2B receptors, although the magnitude of potentiation was not as great as in cell line expressing GluN1/GluN2A. Crystallography and mutagenesis studies revealed that the binding site of GNE-6901 is located at the inter-domain interface between GluN1 and the GluN2A ligand-binding domain (LBD). These results contrast with the GluN2B PAM spermine, which requires the amino-terminal domain (ATD) for PAM effects (Zhu and Paoletti, 2015Zhu S. Paoletti P. Curr. Opin. Pharmacol. 2015; 20: 14-23Crossref PubMed Scopus (113) Google Scholar) but may bear similarity to selective GluN2A and GluN2C/2D NAMs (Costa et al., 2010Costa B.M. Irvine M.W. Fang G. Eaves R.J. Mayo-Martin M.B. Skifter D.A. Jane D.E. Monaghan D.T. J. Pharmacol. Exp. Ther. 2010; 335: 614-621Crossref PubMed Scopus (77) Google Scholar), which target the LBDs. Interestingly, previous reports reveal that other modulators of GluN2A and GluN2B bind to interface of GluN1/Glu2 ATDs (Zhu and Paoletti, 2015Zhu S. Paoletti P. Curr. Opin. Pharmacol. 2015; 20: 14-23Crossref PubMed Scopus (113) Google Scholar). Thus, subunit-subunit interfaces may be key loci for allosteric modulation of NMDAR functions. While these GluN2A PAMs are closely related structural analogs, functional studies revealed subtle differences between the compounds in their effects on channel function. Both GNE-6901 and GNE-8324 increase Glu potency, whereas neither PAM had significant effects on glycine (Gly) potency. Furthermore, both compounds slowed channel deactivation kinetics. However, GNE-8324 caused significantly slower NMDAR current deactivation following the termination of Glu application, compared to GNE-6901. Interestingly, when Gly was removed following the rapid Glu/Gly application in the constant presence of Glu, NMDAR currents rapidly deactivated in the presence of either GNE-6901 or GNE-8324, which is in sharp contrast to the slower NMDAR current deactivation in the presence of GNE-8324 when Gly was not removed. The authors argued that this demonstrated a specific interaction of PAMs with Glu but not Gly. However, these data also suggest that the slower NMDAR current deactivation in the presence of GNE-8324, but not GNE-6901, is highly dependent on ambient Gly concentration. GNE-8324 also markedly increased potency of Glu at GluN1/GluN2A NMDARs by about 10-fold while GNE-6901 had a much smaller effect on Glu potency. Finally GNE-8324 potency was strongly dependent on Glu concentration, whereas Glu concentration had only a modest effect on GNE-6901 potency. The deferential effects of GNE-6901 and GNE-8324 on GluN1/GluN2A NMDAR function could reflect subtle differences in modes of action of these closely related compounds, which might lead to distinct actions on NMDAR modulation in physiological settings. Interestingly, studies in hippocampal slices revealed that GNE-6901 and GNE-8324 display dramatic differences in effects on NMDAR signaling in an intact circuit. GNE-6901 significantly potentiated the NMDAR EPSCs at Shaffer collateral (SC)-CA1 pyramidal cell synapses in WT, but not GluN2A KO, mice. Furthermore, in studies in which inhibitory transmission is intact, GNE-6901 enhanced induction of both short-term potentiation (STP) and LTP at this synapse. These results are consistent with an established role of GluN2A in induction of LTP at this synapse (Sakimura et al., 1995Sakimura K. Kutsuwada T. Ito I. Manabe T. Takayama C. Kushiya E. Yagi T. Aizawa S. Inoue Y. Sugiyama H. et al.Nature. 1995; 373: 151-155Crossref PubMed Scopus (680) Google Scholar) and suggest that the novel GluN2A PAM is efficacious and highly selective in the native tissue. However, further studies revealed fascinating differences in the effects of the two structurally related GluN2A PAMs. Surprisingly, GNE-8324 impaired both STP and LTP at the SC-CA1 synapse. In the presence of a GABAA receptor antagonist, GNE-6901 was still able to potentiate LTP and STP, whereas GNE-8324 lost its ability to reduce the synaptic plasticity. Based on this, the authors examined the effects of the PAMs on NMDAR-mediated synaptic responses in CA1 pyramidal cells and interneurons in the stratum radiatum of CA1 and found that GNE-6901 potentiated synaptic NMDAR responses in both pyramidal cells and interneurons, whereas GNE-8324 potentiated NMDAR responses only in interneurons and not in the pyramidal cells. Furthermore, GNE-6901 enhanced NMDAR EPSPs induced by a burst of stimuli that mimicked the LTP induction protocol in both intact and disinhibited conditions. In contrast, GNE-8324 suppressed the burst-evoked NMDAR EPSPs in slices with intact inhibition, but not in disinhibited slices. These data suggest that subtly different properties of the two PAMs may result in fundamentally different effects in intact circuits. While the precise molecular mechanism underlying this critical difference is not clear, the differential effects of the two PAMs on NMDAR EPSPs in interneurons versus pyramidal cells provide a viable mechanism by which GNE-6901 can enhance STP and LTP, whereas GNE-8324 has the opposite effect in the hippocampus when inhibition was intact. The dramatic differences in GNE-6901 and GNE-8324 on synaptic responses and synaptic plasticity in the hippocampus are reminiscent of differences in effects of structurally similar PAMs for GPCRs (see Conn et al., 2014Conn P.J. Lindsley C.W. Meiler J. Niswender C.M. Nat. Rev. Drug Discov. 2014; 13: 692-708Crossref PubMed Scopus (212) Google Scholar for review). For instance, the presence of allosteric agonist activity of mGlu5 PAMs can lead to induction of epileptiform activity in hippocampal slices and generalized convulsions and cell death in animal models that are not observed with closely related mGlu5 PAMs that lack allosteric agonist activity. Furthermore, multiple studies reveal that GPCR PAMs can display “stimulus bias” and differentially potentiate different responses to receptor activation, and subtle differences in stimulus bias of related PAMs can dramatically impact physiological effects. Finally, GPCR PAMs can differentially impact receptor function depending on the subunit composition of a heteromeric complex, and this translates into dramatic differences in activity at identified synapses. This is analogous to the finding of Hackos et al., 2016Hackos D.H. Lupardus P.J. Grand T. Chen Y. Wang T.-M. Reynen P. Gustafson A. Wallweber H.J.A. Volgraf M. Sellers B.D. et al.Neuron. 2016; 89 (this issue): 983-999Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar that the GluN2A PAMs are less active on GluN1/GluN2A/GluN2B triheteromeric complexes than GluN1/GluN2A diheteromers. The dominant subunit composition of NMDARs at specific synapses in pyramidal cells and inhibitory interneurons could directly impact the effects of different GluN1A PAMs. Another intriguing finding of the current studies is that, while functionally selective for GluN2A-containing NMDARs, some of these novel NMDAR PAMs behaved as neutral allosteric ligands (NALs) at AMPA receptors. While it is tempting to assume that NAL activity observed in cell lines will be functionally irrelevant in native systems, this may not be the case. Studies of GPCR modulators suggest that different allosteric modulators can have fundamentally different effects in different cellular contexts. Thus, a given modulator may behave as a NAL, PAM, or NAM, depending on the cell population, interacting proteins, and other factors, such as phosphorylation state and other posttranslational modifications. Thus, it is conceivable that these compounds could have activity on AMPA and GluN2B receptors in some cellular contexts and that this could differ for closely related GluN2A PAMs. Thus, it is critical to consider the ability of these PAMs to bind other glutamate receptor subtypes and the possibility that this has functional consequences that vary in different cell populations and at different synapses. While these complexities create challenges in interpreting results from studies with allosteric modulators, the impact of different factors in influencing responses to allosteric modulators provides an exciting opportunity to develop an understanding that allows investigators to optimize compounds that have highly specific actions at identified synapses and provide subtle modulation of specific components of CNS circuits. Taken together, the results from these elegant studies suggest that the structurally related GluN2A PAMs, GNE-6901 and GNE-8324, have different modes of action in cell line systems, which translate to their distinct effects in native tissue. These studies should provide a springboard from which to more fully evaluate the roles of specific NMDAR subunits and effects of subunit-selective NMDAR PAMs at specific synapses in intact brain circuits. In the future, it is critically important to optimize NMDAR PAMs that have the pharmacokinetic properties and provide CNS exposure required to advance to in vivo studies and directly translate these findings to in vivo effects of selectively increasing activity NMDAR responses mediated by specific NMDAR subunits. Positive Allosteric Modulators of GluN2A-Containing NMDARs with Distinct Modes of Action and Impacts on Circuit FunctionHackos et al.NeuronFebruary 11, 2016In BriefHackos et al. describe the discovery of positive allosteric modulators of GluN2A NMDA receptors that bind a novel site in the GluN1/GluN2A ligand-binding domain. Modulators with distinct pharmacological properties are then used to probe NMDAR function in brain slices. Full-Text PDF Open Archive" @default.
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• W2289682110 title "Novel PAMs Targeting NMDAR GluN2A Subunit" @default.
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