The Startle Disease Mutation E103K Impairs Activation of Human Homomeric α1 Glycine Receptors by Disrupting an Intersubunit Salt Bridge across the Agonist Binding Site.

Glycine receptors (GlyR) belong to the pentameric ligand-gated ion channel (pLGIC) superfamily and mediate fast inhibitory transmission in the vertebrate CNS. Disruption of glycinergic transmission by inherited mutations produces startle disease in man. Many startle mutations are in GlyRs and provide useful clues to the function of the channel domains. E103K is one of few startle mutations found in the extracellular agonist binding site of the channel, in loop A of the principal side of the subunit interface. Homology modeling shows that the side chain of Glu-103 is close to that of Arg-131, in loop E of the complementary side of the binding site, and may form a salt bridge at the back of the binding site, constraining its size. We investigated this hypothesis in recombinant human α1 GlyR by site-directed mutagenesis and functional measurements of agonist efficacy and potency by whole cell patch clamp and single channel recording. Despite its position near the binding site, E103K causes hyperekplexia by impairing the efficacy of glycine, its ability to gate the channel once bound, which is very high in wild type GlyR. Mutating Glu-103 and Arg-131 caused various degrees of loss-of-function in the action of glycine, whereas mutations in Arg-131 enhanced the efficacy of the slightly bigger partial agonist sarcosine (N-methylglycine). The effects of the single charge-swapping mutations of these two residues were largely rescued in the double mutant, supporting the possibility that they interact via a salt bridge that normally constrains the efficacy of larger agonist molecules.

Advanced Microwave Strategies Facilitate Structural Engineering for Efficient Electrocatalysis.

In the dynamic realm of energy conversion, the demand for efficient electrocatalysis has surged due to the urgent need to seamlessly integrate renewable energy. Traditional electrocatalyst preparation faces challenges like poor controllability, elevated costs, and stringent operational conditions. The introduction of microwave strategies represents a transformative shift, offering rapid response, high-temperature energy, and superior controllability. Notably, non-liquid-phase advanced microwave technology holds promise for introducing novel models and discoveries compared to traditional liquid-phase microwave methods. This review examines the nuanced applications of microwave technology in electrocatalyst structural engineering, emphasizing its pivotal role in the energy paradigm and addressing challenges in conventional methods. The ensuing discussion explores the profound impact of advanced microwave strategies on electrocatalyst structural engineering, highlighting discernible advantages in optimizing performance. Various applications of advanced microwave techniques in electrocatalysis are comprehensively discussed, providing a forward-looking perspective on their untapped potential to propel transformative strides in renewable energy research. It provides a forward-looking perspective, delving into the untapped potential of microwaves to propel transformative strides in renewable energy research.

Hollow sinh-Gaussian beams and their paraxial properties.

A new mathematical model of dark-hollow beams, described as hollow sinh-Gaussian (HsG) beams, has been introduced. The intensity distributions of HsG beams are characterized by a single bright ring along the propagation whose size is determined by the order of beams; the shape of the ring can be controlled by beam width and this leads to the elliptical HsG beams. Propagation characteristics of HsG beams through an ABCD optical system have been researched, they can be regarded as superposition of a series of Hypergeometric-Gaussian (HyGG) beams. As a numerical example, the propagation characteristics of HsG beams in free space have been demonstrated graphically.

Pearson's Principle-Inspired Robust 2D Amorphous Ni-Fe-Co Ternary Hydroxides on Carbon Textile for High-Performance Electrocatalytic Water Splitting.

Layered double hydroxide (LDH) is widely used in electrocatalytic water splitting due to its good structural tunability, high intrinsic activity, and mild synthesis conditions, especially for flexible fiber-based catalysts. However, the poor stability of the interface between LDH and flexible carbon textile prepared by hydrothermal and electrodeposition methods greatly affects its active area and cyclic stability during deformation. Here, we report a salt-template-assisted method for the growth of two-dimensional (2D) amorphous ternary LDH based on dip-rolling technology. The robust and high-dimensional structure constructed by salt-template and fiber could achieve a carbon textile-based water splitting catalyst with high loading, strong catalytic activity, and good stability. The prepared 2D NiFeCo-LDH/CF electrode showed overpotentials of 220 mV and 151 mV in oxygen evolution and hydrogen evolution reactions, respectively, and simultaneously had no significant performance decrease after 100 consecutive bendings. This work provides a new strategy for efficiently designing robust, high-performance LDH on flexible fibers, which may have great potential in commercial applications.

Pharmacological characterization of a novel negative allosteric modulator of NMDA receptors, UBP792.

N-methyl-d-aspartate (NMDA) receptors (NMDARs) are a subtype of ionotropic glutamate receptor with important roles in CNS function. Since excessive NMDAR activity can lead to neuronal cell death and epilepsy, there is interest in developing NMDAR negative allosteric modulators (NAMs) as neuroprotective agents. In this study, we characterize the inhibitory properties of a novel NMDAR antagonist, UBP792. This compound displays partial subtype-selectivity by having a varied maximal inhibition of GluN2A-, GluN2B-, GluN2C-, and GluN2D-containing receptors (52%, 70%, 87%, 89%, respectively) with IC50s 4-10 µM. UBP792 inhibited NMDAR responses by reducing l-glutamate and glycine potencies and efficacies. Consistent with non-competitive inhibition, increasing agonist concentrations 30-fold did not reduce UBP792 potency. UBP792 inhibition was also not competitive with the structurally-related positive allosteric modulator (PAM) UBP684. UBP792 activity was voltage-independent, unaffected by GluN1's exon-5, and reduced at low pH (except for GluN1/GluN2A receptors which were more sensitive at acidic pH). UBP792 binding appeared independent of agonist binding and may be entering the plasma membrane to gain access to its binding site. Inhibition by UBP792 is reduced when the ligand-binding domain (LBD) of the GluN2 subunit, but not that of the GluN1 subunit, is cross-linked in the closed-cleft, activated conformation. Thus, UBP792 may be inhibiting by stabilizing an open GluN2-LBD cleft associated with channel inactivation or by stabilizing downstream closed channel conformations allosterically-coupled to the GluN2-LBD. These findings further expand the repertoire displayed by NMDAR NAMs thus expanding the opportunities for developing NMDAR modulators with the most appropriate selectivity and physiological actions for specific therapeutic indications.

A novel family of negative and positive allosteric modulators of NMDA receptors.

The N-methyl-D-aspartate (NMDA) receptor family regulates various central nervous system functions, such as synaptic plasticity. However, hypo- or hyperactivation of NMDA receptors is critically involved in many neurological and psychiatric conditions, such as pain, stroke, epilepsy, neurodegeneration, schizophrenia, and depression. Consequently, subtype-selective positive and negative modulators of NMDA receptor function have many potential therapeutic applications not addressed by currently available compounds. We have identified allosteric modulators with several novel patterns of NMDA receptor subtype selectivity that have a novel mechanism of action. In a series of carboxylated naphthalene and phenanthrene derivatives, compounds were identified that selectively potentiate responses at GluN1/GluN2A [e.g., 9-iodophenanthrene-3-carboxylic acid (UBP512)]; GluN1/GluN2A and GluN1/GluN2B [9-cyclopropylphenanthrene-3-carboxylic acid (UBP710)]; GluN1/GluN2D [3,5-dihydroxynaphthalene-2-carboxylic acid (UBP551)]; or GluN1/GluN2C and GluN1/GluN2D receptors [6-, 7-, 8-, and 9-nitro isomers of naphth[1,2-c][1,2,5]oxadiazole-5-sulfonic acid (NSC339614)] and have no effect or inhibit responses at the other NMDA receptors. Selective inhibition was also observed; UBP512 inhibits only GluN1/GluN2C and GluN1/GluN2D receptors, whereas 6-bromo-2-oxo-2H-chromene-3-carboxylic acid (UBP608) inhibits GluN1/GluN2A receptors with a 23-fold selectivity compared with GluN1/GluN2D receptors. The actions of these compounds were not competitive with the agonists L-glutamate or glycine and were not voltage-dependent. Whereas the N-terminal regulatory domain was not necessary for activity of either potentiators or inhibitors, segment 2 of the agonist ligand-binding domain was important for potentiating activity, whereas subtype-specific inhibitory activity was dependent upon segment 1. In terms of chemical structure, activity profile, and mechanism of action, these modulators represent a new class of pharmacological agents for the study of NMDA receptor subtype function and provide novel lead compounds for a variety of neurological disorders.

Surface plasmon reflector based on serial stub structure.

Plasmonic reflectors based on serial stub structure are studied in this paper. A general theory of periodic stub structure using transmission line model is developed. The transmission characteristics, e.g., periodicity and symmetry of the spectra, are closely related to the ratio of structure period to stub length. Investigation reveals that the transmission valleys of the spectra could be divided into two categories, which is quite different from conventional Bragg reflectors. Finite-Difference Time-Domain (FDTD) method is used in numerical analysis in this paper.

Dynamic generation of multi-qubit entanglement in the ultrastrong-coupling regime.

We propose a dynamic evolution protocol for generating multi-qubit GHZ states in the ultrastrong-coupling regime of circuit QED. By varying the time length of sequences, the protocol works for any coupling strength g/ωr ≥ 0.25. The time for generating the GHZ states in our protocol can be in the subnanoseconds. By taking into account realistic parameters of circuit QED, the degeneracy of fidelity due to decoherence can be as low as 0.02%.

Positive and Negative Allosteric Modulators of N-Methyl-d-aspartate (NMDA) Receptors: Structure-Activity Relationships and Mechanisms of Action.

Excitatory activity in the CNS is predominately mediated by l-glutamate through several families of l-glutamate neurotransmitter receptors. Of these, the N-methyl-d-aspartate receptor (NMDAR) family has many critical roles in CNS function and in various neuropathological and psychiatric conditions. Until recently, the types of compounds available to regulate NMDAR function have been quite limited in terms of mechanism of action, subtype selectivity, and biological effect. However, several new classes of NMDAR agents have now been identified that are positive or negative allosteric modulators (PAMs and NAMs, respectively) with various patterns of NMDAR subtype selectivity. These new agents act at several newly recognized binding sites on the NMDAR complex and offer significantly greater pharmacological control over NMDAR activity than previously available agents. The purpose of this review is to summarize the structure-activity relationships for these new NMDAR modulator drug classes and to describe the current understanding of their mechanisms of action.

Investigation of the structural requirements for N-methyl-D-aspartate receptor positive and negative allosteric modulators based on 2-naphthoic acid.

The N-methyl-D-aspartate receptor (NMDAR), a ligand-gated ion channel activated by L-glutamate and glycine, plays a major role in the synaptic plasticity underlying learning and memory. NMDARs are involved in neurodegenerative disorders such as Alzheimer's and Parkinson's disease and NMDAR hypofunction is implicated in schizophrenia. Herein we describe structure-activity relationship (SAR) studies on 2-naphthoic acid derivatives to investigate structural requirements for positive and negative allosteric modulation of NMDARs. These studies identified compounds such as UBP684 (14b), which act as pan potentiators by enhancing NMDAR currents in diheteromeric NMDAR tetramers containing GluN1 and GluN2A-D subunits. 14b and derivatives thereof are useful tools to study synaptic function and have potential as leads for the development of drugs to treat schizophrenia and disorders that lead to a loss of cognitive function. In addition, SAR studies have identified a series of styryl substituted compounds with partial NAM activity and a preference for inhibition of GluN2D versus the other GluN2 subunits. In particular, the 3-and 2-nitrostyryl derivatives UBP783 (79i) and UBP792 (79h) had IC50s of 1.4 µM and 2.9 µM, respectively, for inhibition of GluN2D but showed only 70-80% maximal inhibition. GluN2D has been shown to play a role in excessive pain transmission due to nerve injury and potentially in neurodegenerative disorders. Partial GluN2D inhibitors may be leads for the development of drugs to treat these disorders without the adverse effects observed with full NMDAR antagonists.

The NMDA receptor intracellular C-terminal domains reciprocally interact with allosteric modulators.

N-methyl-d-aspartate receptors (NMDARs) have multiple prominent roles in CNS function but their excessive or insufficient activity contributes to neuropathological/psychiatric disorders. Consequently, a variety of positive and negative allosteric modulators (PAMs and NAMs, respectively) have recently been developed. Although these modulators bind to extracellular domains, in the present report we find that the NMDAR's intracellular C-terminal domains (CTDs) significantly influence PAM/NAM activity. GluN2 CTD deletion robustly affected NAM and PAM activity with both enhancing and inhibiting effects that were compound-specific and NMDAR subunit-specific. In three cases, individual PAMs became NAMs at specific GluN2-truncated receptors. In contrast to GluN2, GluN1 CTD removal only reduced PAM activity of UBP684 and CIQ, and did not affect NAM activity. Consistent with these findings, agents altering phosphorylation state or intracellular calcium levels displayed receptor-specific and compound-specific effects on PAM activity. It is possible that the GluN2's M4 domain transmits intracellular modulatory signals from the CTD to the M1/M4 channel gating machinery and that this site is a point of convergence in the direct or indirect actions of several PAMs/NAMs thus rendering them sensitive to CTD status. Thus, allosteric modulators are likely to have a marked and varied sensitivity to post-translational modifications, protein-protein associations, and intracellular ions. The interaction between PAM activity and NMDAR CTDs appears reciprocal. GluN1 CTD-deletion eliminated UBP684, but not pregnenolone sulfate (PS), PAM activity. And, in the absence of agonists, UBP684, but not PS, was able to promote movement of fluorescently-tagged GluN1-CTDs. Thus, it may be possible to pharmacologically target NMDAR metabotropic activity in the absence of channel activation.

A single-channel mechanism for pharmacological potentiation of GluN1/GluN2A NMDA receptors.

NMDA receptors (NMDARs) contribute to several neuropathological processes. Novel positive allosteric modulators (PAMs) of NMDARs have recently been identified but their effects on NMDAR gating remain largely unknown. To this end, we tested the effect of a newly developed molecule UBP684 on GluN1/GluN2A receptors. We found that UBP684 potentiated the whole-cell currents observed under perforated-patch conditions and slowed receptor deactivation. At the single channel level, UBP684 produced a dramatic reduction in long shut times and a robust increase in mean open time. These changes were similar to those produced by NMDAR mutants in which the ligand-binding domains (LBDs) are locked in the closed clamshell conformation by incorporating a disulfide bridge. Since the locked glutamate-binding clefts primarily contributes to receptor efficacy these results suggests that UBP684 binding may induce switch in conformation similar to glutamate LBD locked state. Consistent with this prediction UBP684 displayed greater potentiation of NMDARs with only the GluN1 LBD locked compared to NMDARs with only the GluN2 LBD locked. Docking studies suggest that UBP684 binds to the GluN1 and GluN2 LBD interface supporting its potential ability in stabilizing the LBD closed conformation. Together these studies identify a novel pharmacological mechanism of facilitating the function of NMDARs.

Mechanism and properties of positive allosteric modulation of N-methyl-d-aspartate receptors by 6-alkyl 2-naphthoic acid derivatives.

The theory that N-methyl-d-aspartate receptor (NMDAR) hypofunction is responsible for the symptoms of schizophrenia is well supported by many pharmacological and genetic studies. Accordingly, positive allosteric modulators (PAMs) that augment NMDAR signaling may be useful for treating schizophrenia. Previously we have identified several NMDAR PAMs containing a carboxylic acid attached to naphthalene, phenanthrene, or coumarin ring systems. In this study, we describe several functional and mechanistic properties of UBP684, a 2-naphthoic acid derivative, which robustly potentiates agonist responses at each of the four GluN1a/GluN2 receptors and at neuronal NMDARs. UBP684 increases the maximal l-glutamate/glycine response while having minor subunit-specific effects on agonist potency. PAM binding is independent of agonist binding, and PAM activity is independent of membrane voltage, redox state, and the GluN1 exon 5 N-terminal insert. UBP684 activity is, however, markedly pH-dependent, with greater potentiation occurring at lower pHs and inhibitory activity at pH 8.4. UBP684 increases channel open probability (Po) and slows receptor deactivation time upon removal of l-glutamate, but not glycine. The structurally related PAM, UBP753, reproduced most of these findings, but did not prolong agonist removal deactivation time. Studies using cysteine mutants to lock the GluN1 and GluN2 ligand-binding domains (LBDs) in the agonist-bound states indicate that PAM potentiation requires GluN2 LBD conformational flexibility. Together, these findings suggest that UBP684 and UBP753 stabilize the GluN2 LBD in an active conformation and thereby increase Po. Thus, UBP684 and UBP753 may serve as lead compounds for developing agents to enhance NMDAR activity in disorders associated with NMDAR hypofunction.

Synthesis of a Series of Novel 3,9-Disubstituted Phenanthrenes as Analogues of Known NMDA Receptor Allosteric Modulators.

9-Substituted phenanthrene-3-carboxylic acids have been reported to have allosteric modulatory activity at the NMDA receptor. This receptor is activated by the excitatory neurotransmitter L-glutamate and has been implicated in a range of neurological disorders such as schizophrenia, epilepsy and chronic pain and neurodegenerative disorders such as Alzheimer's disease. Herein, the convenient synthesis of a wide range of novel 3,9-disubstituted phenanthrene derivatives starting from a few common intermediates is described. These new phenanthrene derivatives will help to clarify the structural requirements for allosteric modulation of the NMDA receptor.

Application of Chiral Sulfides to Catalytic Asymmetric Aziridination and Cyclopropanation with In Situ Generation of the Diazo Compound.

Imines and alkenes can be converted into the corresponding aziridines and cyclopropanes (see scheme, PTC=phase-transfer catalyst, Ts=toluene-4-sulfonyl) in good yield with moderate to high d.r. and high ee values using tosylhydrazone salts with catalytic quantities of chiral sulfide (5-20 mol %) and metal catalyst (1 mol %). The process is particularly suited to the synthesis of conformationally locked cyclopropyl amino acids, which can now be prepared in only three steps from commercially available material in 100 % ee.

Characterisation of an mGlu8 receptor-selective agonist and antagonist in the lateral and medial perforant path inputs to the dentate gyrus.

Since its characterisation in 2001, the mGlu8-selective agonist DCPG has been widely used to explore the potential functional role of this group III mGlu receptor within the central nervous system. This research has implicated mGlu8 receptors in a number of disease states and conditions such as epilepsy and anxiety, suggesting that mGlu8-selective ligands may hold important therapeutic potential. However, there is evidence that DCPG exerts off-target effects at higher concentrations, limiting its use as an mGlu8-selective agonist. Here, we have used field recordings in rat hippocampal slices to investigate the effects of DCPG in the lateral perforant path (LPP), a pathway known to express high levels of mGlu8. We show that DCPG does inhibit excitatory transmission in this pathway, but produces a biphasic concentration-response curve suggesting activation of two distinct receptor types. The putative mGlu8-selective antagonist MDCPG antagonises the high, but not the low, potency component of this concentration-response curve. In addition, higher concentrations of DCPG also depress excitatory transmission in the medial perforant path (MPP), a pathway expressing very low levels of mGlu8 receptors. Experiments in slices from mice lacking mGlu8 receptors indicate that concentrations of DCPG >1 µM produce large non-selective effects in both the LPP and MPP. Further experiments in slices from mGlu2, 4 and 7 knock-out mice, as well as in an mGlu2-deficient substrain of Wistar rat, reveal that these non-selective effects are mediated primarily by mGlu2 receptors. Taken together, our results confirm the mGlu8-selectivity of DCPG at submicromolar concentrations, but suggest that care must be taken when employing higher concentrations of the agonist, which may additionally activate mGlu2 receptors, especially at synapses where their expression is high. MDCPG may be a useful tool in determining whether observable DCPG effects are attributable to mGlu8, versus mGlu2, receptor activation.

The NMDA receptor as a target for cognitive enhancement.

NMDA receptors (NMDARs) play an important role in neural plasticity including long-term potentiation and long-term depression, which are likely to explain their importance for learning and memory. Cognitive decline is a major problem facing an ageing human population, so much so that its reversal has become an important goal for scientific research and pharmaceutical development. Enhancement of NMDAR function is a core strategy toward this goal. In this review we indicate some of the major ways of potentiating NMDAR function by both direct and indirect modulation. There is good evidence that both positive and negative modulation can enhance function suggesting that a subtle approach correcting imbalances in particular clinical situations will be required. Excessive activation and the resultant deleterious effects will need to be carefully avoided. Finally we describe some novel positive allosteric modulators of NMDARs, with some subunit selectivity, and show initial evidence of their ability to affect NMDAR mediated events. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Pharmacological modulation of NMDA receptor activity and the advent of negative and positive allosteric modulators.

The NMDA receptor (NMDAR) family of l-glutamate receptors are well known to have diverse roles in CNS function as well as in various neuropathological and psychiatric conditions. Until recently, the types of agents available to pharmacologically regulate NMDAR function have been quite limited in terms of mechanism of action and subtype selectivity. This has changed significantly in the past two years. The purpose of this review is to summarize the many drug classes now available for modulating NMDAR activity. Previously, this included competitive antagonists at the l-glutamate and glycine binding sites, high and low affinity channel blockers, and GluN2B-selective N-terminal domain binding site antagonists. More recently, we and others have identified new classes of NMDAR agents that are either positive or negative allosteric modulators (PAMs and NAMs, respectively). These compounds include the pan potentiator UBP646, the GluN2A-selective potentiator/GluN2C and GluN2D inhibitor UBP512, the GluN2D-selective potentiator UBP551, the GluN2C/GluN2D-selective potentiator CIQ as well as the new NMDAR-NAMs such as the pan-inhibitor UBP618, the GluN2C/GluN2D-selective inhibitor QZN46 and the GluN2A inhibitors UBP608 and TCN201. These new agents do not bind within the l-glutamate or glycine binding sites, the ion channel pore or the N-terminal regulatory domain. Collectively, these new allosteric modulators appear to be acting at multiple novel sites on the NMDAR complex. Importantly, these agents display improved subtype-selectivity and as NMDAR PAMs and NAMs, they represent a new generation of potential NMDAR therapeutics.

Coumarin-3-carboxylic acid derivatives as potentiators and inhibitors of recombinant and native N-methyl-D-aspartate receptors.

N-Methyl-d-aspartate receptors (NMDARs) are known to be involved in a range of neurological and neurodegenerative disorders and consequently the development of compounds that modulate the function of these receptors has been the subject of intense interest. We have recently reported that 6-bromocoumarin-3-carboxylic acid (UBP608) is a negative allosteric modulator with weak selectivity for GluN2A-containing NMDARs. In the present study, a series of commercially available and newly synthesized coumarin derivatives have been evaluated in a structure-activity relationship (SAR) study as modulators of recombinant NMDAR activity. The main conclusions from this SAR study were that substituents as large as iodo were accommodated at the 6-position and that 6,8-dibromo or 6,8-diiodo substitution of the coumarin ring enhanced the inhibitory activity at NMDARs. These coumarin derivatives are therefore excellent starting points for the development of more potent and GluN2 subunit selective inhibitors, which may have application in the treatment of a range of neurological disorders such as neuropathic pain, epilepsy and depression. Surprisingly, 4-methyl substitution of UBP608 to give UBP714, led to conversion of the inhibitory activity of UBP608 into potentiating activity at recombinant GluN1/GluN2 receptors. UBP714 also enhanced NMDAR mediated field EPSPs in the CA1 region of the hippocampus. UBP714 is therefore a novel template for the development of potent and subunit selective NMDAR potentiators that may have therapeutic applicability in the treatment of patients with cognitive deficits or schizophrenia.

Structure-activity relationships for allosteric NMDA receptor inhibitors based on 2-naphthoic acid.

Over-activation of N-methyl-d-aspartate (NMDA) receptors is critically involved in many neurological conditions, thus there has been considerable interest in developing NMDA receptor antagonists. We have recently identified a series of naphthoic and phenanthroic acid compounds that allosterically modulate NMDA receptors through a novel mechanism of action. In the present study, we have determined the structure-activity relationships of 18 naphthoic acid derivatives for the ability to inhibit the four GluN1/GluN2(A-D) NMDA receptor subtypes. 2-Naphthoic acid has low activity at GluN2A-containing receptors and yet lower activity at other NMDA receptors. 3-Amino addition, and especially 3-hydroxy addition, to 2-naphthoic acid increased inhibitory activity at GluN1/GluN2C and GluN1/GluN2D receptors. Further halogen and phenyl substitutions to 2-hydroxy-3-naphthoic acid leads to several relatively potent inhibitors, the most potent of which is UBP618 (1-bromo-2-hydroxy-6-phenylnaphthalene-3-carboxylic acid) with an IC(50) âˆ¼ 2 µM at each of the NMDA receptor subtypes. While UBP618 is non-selective, elimination of the hydroxyl group in UBP618, as in UBP628 and UBP608, leads to an increase in GluN1/GluN2A selectivity. Of the compounds evaluated, specifically those with a 6-phenyl substitution were less able to fully inhibit GluN1/GluN2A, GluN1/GluN2B and GluN1/GluN2C responses (maximal % inhibition of 60-90%). Such antagonists may potentially have reduced adverse effects by not excessively blocking NMDA receptor signaling. Together, these studies reveal discrete structure-activity relationships for the allosteric antagonism of NMDA receptors that may facilitate the development of NMDA receptor modulator agents for a variety of neuropsychiatric and neurological conditions.