Search

The mechanism of tacrine as a precognitive drug has been considered to be complex and not fully understood. It has been reported to involve a wide spectrum of targets involving cholinergic, gabaergic, nitrinergic and glutamatergic pathways. Here, we review the effect of tacrine and its derivatives on the NMDA receptors (NMDAR) with a focus on the mechanism of action and biological consequences related to the Alzheimer's disease treatment. Our findings indicate that effect of tacrine on glutamatergic neurons is both direct and indirect. Direct NMDAR antagonistic effect is often reported by in vitro studies; however, it is achieved by high tacrine concentrations which are not likely to occur under clinical conditions. The impact on memory and behavioral testing can be ascribed to indirect effects of tacrine caused by influencing the NMDAR-mediated currents via M1 receptor activation, which leads to inhibition of Ca 2 + -activated potassium channels. Such inhibition prevents membrane repolarization leading to prolonged NMDAR activation and subsequently to long term potentiation. Considering these findings, we can conclude that tacrine-derivatives with dual cholinesterase and NMDARs modulating activity may represent a promising approach in the drug development for diseases associated with cognitive dysfunction, such as the Alzheimer disease. [ABSTRACT FROM AUTHOR]

N-Methyl-o-aspartate (NMDA) receptors are glutamategated ion channels composed of NR1 and NR2 subunits. When expressed alone, the most prevalent NR1 splice variant and all NR2 subunits are retained in the endoplasmic reticulum (ER), whereas other NR1 splice variants reach the cell surface to varying degrees. Because similar trafficking patterns have been seen for single transmembrane domain chimeric proteins with appended C termini of NMDA receptor subunits, these chimeric proteins have been used as a model for studying the mechanisms underlying the ER retention and surface trafficking of NMDA receptors. Using this approach, an RRR motif in the C1 cassette has been identified as a major ER retention signal present in NR1 subunits, and the surface localization of other NR1 splice variants has been explained by the absence of the C1 cassette or by the presence of a PDZ/coatomer protein complex IL-binding domain in the C2′ cassette. However, when we tested these conclusions using full-length NR1 constructs, a more complex role of the C-terminal cassettes in the trafficking of NR1 subunits emerged. Our experiments showed that two independent ER retention motifs in the C1 cassette, KKK and RRR, are the signals mediating ER retention of the full-length NR1 subunits and that the C2 cassette has an additional inhibitory effect on the forward trafficking of NR1 subunits. On the other hand, CO and C2′ cassettes had an enhancing effect on the trafficking of NR1 subunits to the cell surface. Our observations identify the unique roles of C-terminal cassettes in the trafficking of full-length NR1 subunits. [ABSTRACT FROM AUTHOR]

The Lémann Index is a tool measuring cumulative structural bowel damage in Crohn's disease (CD). We reported on its validation and updating. This was an international, multicenter, prospective, cross-sectional observational study. At each center, 10 inclusions, stratified by CD duration and location, were planned. For each patient, the digestive tract was divided into 4 organs, upper tract, small bowel, colon/rectum, anus, and subsequently into segments, explored systematically by magnetic resonance imaging and by endoscopies in relation to disease location. For each segment, investigators retrieved information on previous surgical procedures, identified predefined strictures and penetrating lesions of maximal severity (grades 1–3) at each organ investigational method (gastroenterologist and radiologist for magnetic resonance imaging), provided segmental damage evaluation ranging from 0.0 to 10.0 (complete resection). Organ resection-free cumulative damage evaluation was then calculated from the sum of segmental damages. Then investigators provided a 0–10 global damage evaluation from the 4-organ standardized cumulative damage evaluations. Simple linear regressions of investigator damage evaluations on their corresponding Lémann Index were studied, as well as calibration plots. Finally, updated Lémann Index was derived through multiple linear mixed models applied to combined development and validation samples. In 15 centers, 134 patients were included. Correlation coefficients between investigator damage evaluations and Lémann Indexes were >0.80. When analyzing data in 272 patients from both samples and 27 centers, the unbiased correlation estimates were 0.89, 0,97, 0,94, 0.81, and 0.91 for the 4 organs and globally, and stable when applied to one sample or the other. The updated Lémann Index is a well-established index to assess cumulative bowel damage in CD that can be used in epidemiological studies and disease modification trials. [ABSTRACT FROM AUTHOR]

Therapeutic options for Alzheimer's disease are limited. Dual compounds targeting two pathways concurrently may enable enhanced effect. The study focuses on tacrine derivatives inhibiting acetylcholinesterase (AChE) and simultaneously N-methyl-D-aspartate (NMDA) receptors. Compounds with balanced inhibitory potencies for the target proteins (K1578 and K1599) or increased potency for AChE (K1592 and K1594) were studied to identify the most promising pro-cognitive compound. Their effects were studied in cholinergic (scopolamine-induced) and glutamatergic (MK-801-induced) rat models of cognitive deficits in the Morris water maze. Moreover, the impacts on locomotion in the open field and AChE activity in relevant brain structures were investigated. The effect of the most promising compound on NMDA receptors was explored by in vitro electrophysiology. The cholinergic antagonist scopolamine induced a deficit in memory acquisition, however, it was unaffected by the compounds, and a deficit in reversal learning that was alleviated by K1578 and K1599. K1578 and K1599 significantly inhibited AChE in the striatum, potentially explaining the behavioral observations. The glutamatergic antagonist dizocilpine (MK-801) induced a deficit in memory acquisition, which was alleviated by K1599. K1599 also mitigated the MK-801-induced hyperlocomotion in the open field. In vitro patch-clamp corroborated the K1599-associated NMDA receptor inhibitory effect. K1599 emerged as the most promising compound, demonstrating pro-cognitive efficacy in both models, consistent with intended dual effect. We conclude that tacrine has the potential for development of derivatives with dual in vivo effects. Our findings contributed to the elucidation of the structural and functional properties of tacrine derivatives associated with optimal in vivo pro-cognitive efficacy. [Display omitted] • Tacrine derivatives inhibiting cholinesterase and NMDA receptors as Alzheimer's drugs. • Effects on rat cholinergic and glutamatergic models of cognitive deficits explored. • Compound K1599 mitigated cognitive deficits in both models - dual effect in vivo. • Acetylcholinesterase inhibition in brain structures may explain behavioral effects. • Interaction of K1599 with NMDA receptors investigated by patch-clamp. [ABSTRACT FROM AUTHOR]

The search for novel drugs to address the medical needs of Alzheimer's disease (AD) is an ongoing process relying on the discovery of disease-modifying agents. Given the complexity of the disease, such an aim can be pursued by developing so-called multi-target directed ligands (MTDLs) that will impact the disease pathophysiology more comprehensively. Herewith, we contemplated the therapeutic efficacy of an amiridine drug acting as a cholinesterase inhibitor by converting it into a novel class of novel MTDLs. Applying the linking approach, we have paired amiridine as a core building block with memantine/adamantylamine, trolox, and substituted benzothiazole moieties to generate novel MTDLs endowed with additional properties like N -methyl- d -aspartate (NMDA) receptor affinity, antioxidant capacity, and anti-amyloid properties, respectively. The top-ranked amiridine-based compound 5d was also inspected by in silico to reveal the butyrylcholinesterase binding differences with its close structural analogue 5b. Our study provides insight into the discovery of novel amiridine-based drugs by broadening their target-engaged profile from cholinesterase inhibitors towards MTDLs with potential implications in AD therapy. [Display omitted] • Novel amiridine-based drugs were developed addressing Alzheimer's complexity • Compounds were designed pursuing multi-target directed ligand approach • Amiridine was combined with memantine, trolox and benzothiazole moieties • Compound 5d turned out to be potent and selective butyrylcholinesterase inhibitor • Study provides insights into amiridine's potential beyond cholinesterase inhibition [ABSTRACT FROM AUTHOR]

N -methyl- d -aspartate receptors (NMDARs) are ionotropic glutamate receptors that mediate excitatory neurotransmission in the mammalian central nervous system (CNS), and their dysregulation results in the aetiology of many CNS syndromes. Several NMDAR modulators have been used successfully in clinical trials (including memantine) and NMDARs remain a promising pharmacological target for the treatment of CNS syndromes. 1,2,3,4-Tetrahydro-9-aminoacridine (tacrine; THA) was the first approved drug for Alzheimer's disease (AD) treatment. 7-methoxyderivative of THA (7-MEOTA) is less toxic and showed promising results in patients with tardive dyskinesia. We employed electrophysiological recordings in HEK293 cells and rat neurones to examine the mechanism of action of THA and 7-MEOTA at the NMDAR. We showed that both THA and 7-MEOTA are “foot-in-the-door” open-channel blockers of GluN1/GluN2 receptors and that 7-MEOTA is a more potent but slower blocker than THA. We found that the IC 50 values for THA and 7-MEOTA exhibited the GluN1/GluN2A < GluN1/GluN2B < GluN1/GluN2C = GluN1/GluN2D relationship and that 7-MEOTA effectively inhibits human GluN1/GluN2A-M817V receptors that carry a pathogenic mutation. We also showed that 7-MEOTA is a “foot-in-the-door” open-channel blocker of GluN1/GluN3 receptors, although these receptors were not inhibited by memantine. In addition, the inhibitory potency of 7-MEOTA at synaptic and extrasynaptic hippocampal NMDARs was similar, and 7-MEOTA exhibited better neuroprotective activity when compared with THA and memantine in rats with NMDA-induced lesions of the hippocampus. Finally, intraperitoneal administration of 7-MEOTA attenuated MK-801-induced hyperlocomotion and pre-pulse inhibition deficit in rats. We conclude that 7-MEOTA may be considered for the treatment of diseases associated with the dysfunction of NMDARs. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and currently there is no efficient treatment. The classic drug-design strategy based on the “one-molecule-one-target” paradigm was found to be ineffective in the case of multifactorial diseases like AD. A novel multi-target-directed ligand strategy based on the assumption that a single compound consisting of two or more distinct pharmacophores is able to hit multiple targets has been proposed as promising. Herein, we investigated 7-methoxytacrine - memantine heterodimers developed with respect to the multi-target-directed ligand theory. The spectroscopic, microscopic and cell culture methods were used for systematic investigation of the interference of the heterodimers with β -secretase (BACE1) activity, A β peptide amyloid fibrillization (amyloid theory) and interaction with M1 subtype of muscarinic (mAChRs), nicotinic (nAChRs) acetylcholine receptors (cholinergic theory) and N -methyl- d -aspartate receptors (NMDA) (glutamatergic theory). The drug-like properties of selected compounds have been evaluated from the point of view of blood-brain barrier penetration and cell proliferation. We have confirmed the multipotent effect of novel series of compounds. They inhibited effectively A β peptide amyloid fibrillization and affected the BACE1 activity. Moreover, they have AChE inhibitory potency but they could not potentiate cholinergic transmission via direct interaction with cholinergic receptors. All compounds were reported to act as an antagonist of both M1 muscarinic and muscle-type nicotinic receptors. We have found that 7-methoxytacrine - memantine heterodimers are able to hit multiple targets associated with Alzheimer's disease and thus, have a potential clinical impact for slowing or blocking the neurodegenerative process related to this disease. [ABSTRACT FROM AUTHOR]

Background Hip fractures are mainly caused by accidental falls and trips, which magnify forces in well-defined areas of the proximal femur. Unfortunately, the same areas are at risk of rapid bone loss with ageing, since they are relatively stress-shielded during walking and sitting. Focal osteoporosis in those areas may contribute to fracture, and targeted 3D measurements might enhance hip fracture prediction. In the FEMCO case-control clinical study, Cortical Bone Mapping (CBM) was applied to clinical computed tomography (CT) scans to define 3D cortical and trabecular bone defects in patients with acute hip fracture compared to controls. Direct measurements of trabecular bone volume were then made in biopsies of target regions removed at operation. Methods The sample consisted of CT scans from 313 female and 40 male volunteers (158 with proximal femoral fracture, 145 age-matched controls and 50 fallers without hip fracture). Detailed Cortical Bone Maps (c.5580 measurement points on the unfractured hip) were created before registering each hip to an average femur shape to facilitate statistical parametric mapping (SPM). Areas where cortical and trabecular bone differed from controls were visualised in 3D for location, magnitude and statistical significance. Measures from the novel regions created by the SPM process were then tested for their ability to classify fracture versus control by comparison with traditional CT measures of areal Bone Mineral Density (aBMD). In women we used the surgical classification of fracture location (‘femoral neck’ or ‘trochanteric’) to discover whether focal osteoporosis was specific to fracture type. To explore whether the focal areas were osteoporotic by histological criteria, we used micro CT to measure trabecular bone parameters in targeted biopsies taken from the femoral heads of 14 cases. Results Hip fracture patients had distinct patterns of focal osteoporosis that determined fracture type, and CBM measures classified fracture type better than aBMD parameters. CBM measures however improved only minimally on aBMD for predicting any hip fracture and depended on the inclusion of trabecular bone measures alongside cortical regions. Focal osteoporosis was confirmed on biopsy as reduced sub-cortical trabecular bone volume. Conclusion Using 3D imaging methods and targeted bone biopsy, we discovered focal osteoporosis affecting trabecular and cortical bone of the proximal femur, among men and women with hip fracture. [ABSTRACT FROM AUTHOR]

N -methyl- D -aspartate receptors (NMDARs) play an essential role in excitatory neurotransmission in the mammalian brain, and their physiological importance is underscored by the large number of pathogenic mutations that have been identified in the receptor's GluN subunits and associated with a wide range of diseases and disorders. Here, we characterized the functional and pharmacological effects of the pathogenic N650K variant in the GluN1 subunit, which is associated with developmental delay and seizures. Our microscopy experiments showed that when expressed in HEK293 cells (from ATCC®), the GluN1-N650K subunit increases the surface expression of both GluN1/GluN2A and GluN1/GluN2B receptors, but not GluN1/GluN3A receptors, consistent with increased surface expression of the GluN1-N650K subunit expressed in hippocampal neurons (from embryonic day 18 of Wistar rats of both sexes). Using electrophysiology, we found that the GluN1-N650K variant increases the potency of GluN1/GluN2A receptors to both glutamate and glycine but decreases the receptor's conductance and open probability. In addition, the GluN1-N650K subunit does not form functional GluN1/GluN2B receptors but does form fully functional GluN1/GluN3A receptors. Moreover, in the presence of extracellular Mg2+, GluN1-N650K/GluN2A receptors have a similar and increased response to ketamine and memantine, respectively, while the effect of both drugs had markedly slower onset and offset compared to wild-type GluN1/GluN2A receptors. Finally, we found that expressing the GluN1-N650K subunit in hippocampal neurons reduces excitotoxicity, and memantine shows promising neuroprotective effects in neurons expressing either wild-type GluN1 or the GluN1-N650K subunit. This study provides the functional and pharmacological characterization of NMDARs containing the GluN1-N650K variant. • We studied the properties of NMDA receptors consisting of GluN1 subunits with the pathogenic N650K variant. • This variant increases the surface expression of GluN1/GluN2 but not GluN1/GluN3A receptors. • This variant decreases open probability of GluN1/GluN2 receptors. • This variant affects NMDA receptor inhibition by memantine and ketamine. [ABSTRACT FROM AUTHOR]

NMDA receptors (NMDARs) comprise a subclass of neurotransmitter receptors whose surface expression is regulated at multiple levels, including processing in the endoplasmic reticulum (ER), intracellular trafficking via the Golgi apparatus, internalization, recycling, and degradation. With respect to early processing, NMDARs are regulated by the availability of GluN subunits within the ER, the presence of ER retention and export signals,andposttranslationalmodifications,includingphosphorylation and palmitoylation. However, the role of N-glycosylation, one of the most common posttranslational modifications, in regulating NMDAR processing has not been studied in detail. Using biochemistry, confocal and electron microscopy, and electrophysiology in conjunction with a lentivirus-based molecular replacement strategy, we found that NMDARs are released from the ER only when two asparagine residues in the GluN1 subunit (Asn-203 and Asn-368) are N-glycosylated. Although the GluN2A and GluN2B subunits are also N-glycosylated, their N-glycosylation sites do not appear to be essential for surface delivery of NMDARs. Furthermore, we found that removing N-glycans from native NMDAR saltered the receptor affinity for glutamate. Our results suggest a novel mechanism by which neurons ensure that postsynaptic membranes contain sufficient numbers of functional NMDARs. [ABSTRACT FROM AUTHOR]

N-methyl-D-aspartate (NMDA) receptors are glutamate ionotropic receptors that play critical roles in synaptic transmission, plasticity, and excitotoxicity. The functional NMDA receptors, heterotetramers composed mainly of two NR1 and two NR2 subunits, likely pass endoplasmic reticulum quality control before they are released from the endoplasmic reticulum and trafficked to the cell surface. However, the mechanism underlying this process is not clear. Using truncated and mutated NMDA receptor subunits expressed in heterologous cells, we found that the M3 domains of both NR1 and NR2 subunits contain key amino acid residues that contribute to the regulation of the number of surface functional NMDA receptors. These key residues are critical neither for the interaction between the NR1 and NR2 subunits nor for the formation of the functional receptors, but rather they regulate the early trafficking of the receptors. We also found that the identified key amino acid residues within both NR1 and NR2 M3 domains contribute to the regulation of the surface expression of unassembled NR1 and NR2 subunits. Thus, our data identify the unique role of the membrane domains in the regulation of the number of surface NMDA receptors. [ABSTRACT FROM AUTHOR]

Abstract: Glutamate is the main neurotransmitter released at synapses in the central nervous system of vertebrates. Its excitatory role is mediated through activation of specific glutamatergic ionotropic receptors, among which the N-methyl-d-aspartate (NMDA) receptor subtype has attracted considerable attention in recent years. Substantial progress has been made in elucidating the roles these receptors play under physiological and pathological conditions and in our understanding of the functional, structural, and pharmacological properties of NMDA receptors. Many pharmacological compounds have been identified that affect the activity of NMDA receptors, including neurosteroids. This review summarizes our knowledge about molecular mechanisms underlying the neurosteroid action at NMDA receptors as well as about the action of neurosteroids in animal models of human diseases. [Copyright &y& Elsevier]

Tacrine is a classic drug whose efficacy against neurodegenerative diseases is still shrouded in mystery. It seems that besides its inhibitory effect on cholinesterases, the clinical benefit is co-determined by NMDAR-antagonizing activity. Our previous data showed that the direct inhibitory effect of tacrine, as well as its 7-methoxy derivative (7-MEOTA), is ensured via a "foot-in-the-door" open-channel blockage, and that interestingly both tacrine and 7-MEOTA are slightly more potent at the GluN1/GluN2A receptors when compared with the GluN1/GluN2B receptors. Here, we report that in a series of 30 novel tacrine derivatives, designed for assessment of structure-activity relationship, blocking efficacy differs among different compounds and receptors using electrophysiology with HEK293 cells expressing the defined types of NMDARs. Selected compounds (4 and 5) potently inhibited both GluN1/GluN2A and GluN1/GluN2B receptors; other compounds (7 and 23) more effectively inhibited the GluN1/GluN2B receptors; or the GluN1/GluN2A receptors (21 and 28). QSAR study revealed statistically significant model for the data obtained for inhibition of GluN1/Glu2B at −60 mV expressed as IC 50 values, and for relative inhibition of GluN1/Glu2A at +40 mV caused by a concentration of 100 μM. The models can be utilized for a ligand-based virtual screening to detect potential candidates for inhibition of GluN1/Glu2A and/or GluN1/Glu2B subtypes. Using in vivo experiments in rats we observed that unlike MK-801, the tested novel compounds did not induce hyperlocomotion in open field, and also did not impair prepulse inhibition of startle response, suggesting minimal induction of psychotomimetic side effects. We conclude that tacrine derivatives are promising compounds since they are centrally available subtype-specific inhibitors of the NMDARs without detrimental behavioral side-effects. [Display omitted] • A series of 30 tacrine derivatives were designed and synthesized. • SAR analysis on anticholinesterase and QSAR analysis NMDA receptors activity is reported. • NMDA receptors inhibition significantly differs among the compounds. • Highlighted compounds with promising anti-ChE and NMDA activity are centrally active. • Top-ranked compounds were devoid of detrimental behavioral side-effects. [ABSTRACT FROM AUTHOR]

N -methyl- d -aspartate receptors (NMDARs) play an essential role in regulating glutamatergic neurotransmission. Recently, pathogenic missense mutations were identified in genes encoding NMDAR subunits; however, their effect on NMDAR activity is often poorly understood. Here, we examined whether three previously identified pathogenic mutations (M641I, A645S, and Y647S) in the M3 domain of the GluN1 subunit affect the receptor's surface delivery, agonist sensitivity, Mg2+ block, and/or inhibition by the FDA-approved NMDAR blocker memantine. When expressed in HEK293 cells, we found reduced surface expression of GluN1-M641I/GluN2A, GluN1-Y647S/GluN2A, and GluN1-Y647S/GluN2B receptors; other mutation-bearing NMDAR combinations, including GluN1/GluN3A receptors, were expressed at normal surface levels. When expressed in rat hippocampal neurons, we consistently found reduced surface expression of the GluN1-M641I and GluN1-Y647S subunits when compared with wild-type GluN1 subunit. At the functional level, we found that GluN1-M641I/GluN2 and GluN1-A645S/GluN2 receptors expressed in HEK293 cells have wild-type EC 50 values for both glutamate and glycine; in contrast, GluN1-Y647S/GluN2 receptors do not produce glutamate-induced currents. In the presence of a physiological concentration of Mg2+, we found that GluN1-M641I/GluN2 receptors have a lower memantine IC 50 and slower offset kinetics, whereas GluN1-A645S/GluN2 receptors have a higher memantine IC 50 and faster offset kinetics when compared to wild-type receptors. Finally, we found that memantine was the most neuroprotective in hippocampal neurons expressing GluN1-M641I subunits, followed by neurons expressing wild-type GluN1 and then GluN1-A645S subunits in an NMDA-induced excitotoxicity assay. These results indicate that specific pathogenic mutations in the M3 domain of the GluN1 subunit differentially affect the trafficking and functional properties of NMDARs. • We studied NMDA receptors containing three pathogenic mutations in the GluN1 subunit. • These pathogenic mutations alter surface numbers of specific GluN1/GluN2 receptors. • Two of the mutations alter the sensitivity of the NMDA receptor to memantine. • Altered sensitivity to memantine correlates with its neuroprotective effect. [ABSTRACT FROM AUTHOR]

[Display omitted] N -methyl-D-aspartaterecepro receptor (NMDARs) are a subclass of glutamate receptors, which play an essential role in excitatory neurotransmission, but their excessive overactivation by glutamate leads to excitotoxicity. NMDARs are hence a valid pharmacological target for the treatment of neurodegenerative disorders; however, novel drugs targeting NMDARs are often associated with specific psychotic side effects and abuse potential. Motivated by currently available treatment against neurodegenerative diseases involving the inhibitors of acetylcholinesterase (AChE) and NMDARs, administered also in combination, we developed a dually-acting compound 7-phenoxytacrine (7-PhO-THA) and evaluated its neuropsychopharmacological and drug-like properties for potential therapeutic use. Indeed, we have confirmed the dual potency of 7-PhO-THA, i.e. potent and balanced inhibition of both AChE and NMDARs. We discovered that it selectively inhibits the GluN1/GluN2B subtype of NMDARs via an ifenprodil-binding site, in addition to its voltage-dependent inhibitory effect at both GluN1/GluN2A and GluN1/GluN2B subtypes of NMDARs. Furthermore, whereas NMDA-induced lesion of the dorsal hippocampus confirmed potent anti-excitotoxic and neuroprotective efficacy, behavioral observations showed also a cholinergic component manifesting mainly in decreased hyperlocomotion. From the point of view of behavioral side effects, 7-PhO-THA managed to avoid these, notably those analogous to symptoms of schizophrenia. Thus, CNS availability and the overall behavioral profile are promising for subsequent investigation of therapeutic use. [ABSTRACT FROM AUTHOR]

N -methyl- d -aspartate receptors (NMDARs) play an essential role in excitatory neurotransmission within the mammalian central nervous system (CNS). NMDARs are heteromultimers containing GluN1, GluN2, and/or GluN3 subunits, thus giving rise to a wide variety of subunit combinations, each with unique functional and pharmacological properties. Importantly, GluN1/GluN3A and GluN1/GluN3B receptors form glycine-gated receptors. Here, we combined electrophysiology with rapid solution exchange in order to determine whether the presence of specific N -glycans and/or interactions with specific lectins regulates the functional properties of GluN1/GluN3A and GluN1/GluN3B receptors expressed in human embryonic kidney 293 (HEK293) cells. We found that removing putative N -glycosylation sites alters the functional properties of GluN1/GluN3B receptors, but has no effect on GluN1/GluN3A receptors. Moreover, we found that the functional properties of both GluN1/GluN3A and GluN1/GluN3B receptors are modulated by a variety of lectins, including Concanavalin A (ConA), Wheat Germ Agglutinin (WGA), and Aleuria Aurantia Lectin (AAL), and this effect is likely mediated by a reduction in GluN1 subunit-mediated desensitization. We also found that AAL has the most profound effect on GluN1/GluN3 receptors, and this effect is mediated partly by a single N -glycosylation site on the GluN3 subunit (specifically, N565 on GluN3A and N465 on GluN3B). Finally, we found that lectins mediate their effect only when applied to non-activated receptors and have no effect when applied in the continuous presence of glycine. These findings provide further evidence to distinguish GluN1/GluN3 receptors from the canonical GluN1/GluN2 receptors and offer insight into how GluN1/GluN3 receptors may be regulated in the mammalian CNS. • NMDA receptors play a key role in mediating mammalian excitatory neurotransmission. • GluN1/GluN3 NMDA receptors exhibit unique functional and pharmacological properties. • We show that lectins reduce desensitization of GluN1/GluN3 NMDA receptors. • Our data further distinguish GluN1/GluN3 receptors from GluN1/GluN2 NMDA receptors. [ABSTRACT FROM AUTHOR]