Ligands of the AMPA-subtype glutamate receptors: mechanisms of action and novel chemotypes

Radchenko, Eugene V.; Tarakanova, Anna; Karlov, Dmitry S.; Lavrov, Mstislav I.; Palyulin, Vladimir A.

doi:10.18097/pbmc20216703187

Cited by 6 publications

(3 citation statements)

References 97 publications

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“…The sequence diagram of the ultrasound stimulation was shown. 500 kHz pulse repetition frequency (PRF), 300 ms sonication duration (SD) and 50% duty cycle (DC) 23 were used across all the ultrasound experiments (figure 1D).…”

Section: Resultsmentioning

confidence: 99%

Low-intensity focused ultrasound stimulation promotes stroke recovery via astrocytic HMGB1 and CAMK2N1 in mice

Qi,

Wang,

Deng

et al. 2024

Stroke Vasc Neurol

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BackgroundLow-intensity focused ultrasound stimulation (LIFUS) has been developed to enhance neurological repair and remodelling during the late acute stage of ischaemic stroke in rodents. However, the cellular and molecular mechanisms of neurological repair and remodelling after LIFUS in ischaemic stroke are unclear.MethodsUltrasound stimulation was treated in adult male mice 7 days after transient middle cerebral artery occlusion. Angiogenesis was measured by laser speckle imaging and histological analyses. Electromyography and fibre photometry records were used for synaptogenesis. Brain atrophy volume and neurobehaviour were assessed 0–14 days after ischaemia. iTRAQ proteomic analysis was performed to explore the differentially expressed protein. scRNA-seq was used for subcluster analysis of astrocytes. Fluorescence in situ hybridisation and Western blot detected the expression of HMGB1 and CAMK2N1.ResultsOptimal ultrasound stimulation increased cerebral blood flow, and improved neurobehavioural outcomes in ischaemic mice (p<0.05). iTRAQ proteomic analysis revealed that the expression of HMGB1 increased and CAMK2N1 decreased in the ipsilateral hemisphere of the brain at 14 days after focal cerebral ischaemia with ultrasound treatment (p<0.05). scRNA-seq revealed that this expression pattern belonged to a subcluster of astrocytes after LIFUS in the ischaemic brain. LIFUS upregulated HMGB1 expression, accompanied by VEGFA elevation compared with the control group (p<0.05). Inhibition of HMGB1 expression in astrocytes decreased microvessels counts and cerebral blood flow (p<0.05). LIFUS reduced CAMK2N1 expression level, accompanied by increased extracellular calcium ions and glutamatergic synapses (p<0.05). CAMK2N1 overexpression in astrocytes decreased dendritic spines, and aggravated neurobehavioural outcomes (p<0.05).ConclusionOur results demonstrated that LIFUS promoted angiogenesis and synaptogenesis after focal cerebral ischaemia by upregulating HMGB1 and downregulating CAMK2N1 in a subcluster of astrocytes, suggesting that LIFUS activated specific astrocyte subcluster could be a key target for ischaemic brain therapy.

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Section: Resultsmentioning

confidence: 99%

Low-intensity focused ultrasound stimulation promotes stroke recovery via astrocytic HMGB1 and CAMK2N1 in mice

Qi,

Wang,

Deng

et al. 2024

Stroke Vasc Neurol

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“…The influence of the compound 6 on the kainate-induced currents is shown in Table 2. The potentiation of the kainate-induced AMPA receptor currents was observed in a wide concentration range (10 -12 -10 -6 M) and had a bell-shaped concentration dependence with maximum potentiation at 10 -11 M. As can be seen, the activity of the compound 6 was comparable or superior, in terms of effective concentration and/or maximum potentiation, to that of some of the most potent known positive modulators of the AMPA receptor 8, 9, and was significantly higher than that of cyclothiazide (CTZ) (Figure 2) [29,32,44]. Scheme 4.…”

Section: Electrophysiological Evaluationmentioning

confidence: 91%

A Facile Approach to Bis(isoxazoles), Promising Ligands of the AMPA Receptor

et al. 2021

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A convenient synthetic approach to novel functionalized bis(isoxazoles), the promising bivalent ligands of the AMPA receptor, was elaborated. It was based on the heterocyclization reactions of readily available electrophilic alkenes with the tetranitromethane-triethylamine complex. The structural diversity of the synthesized compounds was demonstrated. In the electrophysiological experiments using the patch clamp technique on Purkinje neurons, the compound 1,4-phenylenedi(methylene)bis(5-aminoisoxazole-3-carboxylate) was shown to be highly potent positive modulator of the AMPA receptor, potentiating kainate-induced currents up to 70% at 10−11 M.

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“…It plays an important role in the functioning of the central nervous system (CNS) and the pathogenesis of many neurological and neurodegenerative diseases. The diversity of its functions is supported by a wide range of receptors belonging to two families: ionotropic glutamate receptors (iGluRs), which represent ligand-gated ion channels, and metabotropic glutamate receptors (mGluRs), which are G protein-coupled receptors [ 1 , 2 , 3 , 4 ]. One of the subtypes of iGluRs are AMPA receptors (AMPARs), selectively activated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), which are present in the CNS in the largest amount, and are characterized by the fastest signal transmission.…”

Section: Introductionmentioning

confidence: 99%

Novel Nanomolar Allosteric Modulators of AMPA Receptor of Bis(pyrimidine) Series: Synthesis, Biotesting and SAR Analysis

et al. 2022

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Positive allosteric modulators (PAMs) of AMPA receptors represent attractive candidates for the development of drugs for the treatment of cognitive and neurodegenerative disorders. Dimeric molecules have been reported to have an especially potent modulating effect, due to the U-shaped form of the AMPA receptor’s allosteric binding-site. In the present work, novel bis(pyrimidines) were studied as AMPA receptor modulators. A convenient and flexible preparative approach to bis(pyrimidines) containing a hydroquinone linker was elaborated, and a series of derivatives with varied substituents was obtained. The compounds were examined in the patch clamp experiments for their influence on the kainate-induced currents, and 10 of them were found to have potentiating properties. The best potency was found for 2-methyl-4-(4-((2-methyl-5,6,7,8-tetrahydroquinazolin-4-yl)oxy)phenoxy)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine, which potentiated the kainate-induced currents by up to 77% in all tested concentrations (10−12–10−6 M). The results were rationalized via the modeling of modulator complexes with the dimeric ligand binding domain of the GluA2 AMPA receptor, using molecular docking and molecular dynamics simulation. The prediction of ADMET, physicochemical, and PAINS properties of the studied bis(pyrimidines) confirmed that PAMs of this type may act as the potential lead compounds for the development of neuroprotective drugs.

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Ligands of the AMPA-subtype glutamate receptors: mechanisms of action and novel chemotypes

Cited by 6 publications

References 97 publications

Low-intensity focused ultrasound stimulation promotes stroke recovery via astrocytic HMGB1 and CAMK2N1 in mice

Low-intensity focused ultrasound stimulation promotes stroke recovery via astrocytic HMGB1 and CAMK2N1 in mice

A Facile Approach to Bis(isoxazoles), Promising Ligands of the AMPA Receptor

Novel Nanomolar Allosteric Modulators of AMPA Receptor of Bis(pyrimidine) Series: Synthesis, Biotesting and SAR Analysis

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