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  • ||||||||||  A synapse chemogenetic tool to elucidate the regulation of sleep need by prefrontal synaptic strength (MCP Hall A) -  Aug 22, 2024 - Abstract #Neuroscience2024Neuroscience_6254;    
    Furthermore, we utilized an excitatory-inhibitory neural network model to predict that an increase in excitatory synaptic strength in cortical excitatory neurons induces periodical hyperpolarized inactive periods (down state), leading to an elevation in simulated delta power. Therefore, we propose a new chemogenetic tool SYNCit-K to induce LTP and a regulatory mechanism whereby sleep need is encoded in the synaptic strength of PFC excitatory neurons, and that this, in turn, promotes deeper NREM sleep.
  • ||||||||||  Postsynaptic Function of cAMP Degrading Phosphodiesterase PDE4A5 in Modulation of AMPA Receptors (MCP Hall A) -  Aug 22, 2024 - Abstract #Neuroscience2024Neuroscience_960;    
    Since the precise functional role of PDE4A5 and its association with PSD-95 is implicated in the trafficking of AMPA receptors, elucidating this relationship expands our understanding of fundamental brain processes. Moreover, it offers promise for developing targeted therapeutic interventions for cognitive disorders, particularly those associated with sleep deprivation and memory consolidation.
  • ||||||||||  Review, Journal:  Structural dynamics in ?-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor gating. (Pubmed Central) -  Jul 28, 2024   
    Additionally, interactions with auxiliary subunits, including transmembrane AMPA-receptor regulatory proteins, germ-cell-specific gene 1-like protein, and cornichon homologs, intricately modulate AMPA receptors. We discuss the recent high-resolution structures of these complexes that unveil stoichiometry, subunit positioning, and differences in specific side-chain interactions that influence these functional modulations.
  • ||||||||||  Review, Journal:  Advances in attenuating opioid-induced respiratory depression: A narrative review. (Pubmed Central) -  Jul 19, 2024   
    At present, the focus is mainly on the development of new opioids with weak respiratory inhibition or the use of non-opioid drugs to stimulate breathing. This review reports recent advances in novel opioid agents, such as mixed opioid receptor agonists, peripheral selective opioid receptor agonists, opioid receptor splice variant agonists, biased opioid receptor agonists, and allosteric modulators of opioid receptors, as well as in non-opioid agents, such as AMPA receptor modulators, 5-hydroxytryptamine receptor agonists, phosphodiesterase-4 inhibitors, and nicotinic acetylcholine receptor agonists.
  • ||||||||||  CX1739 / RespireRx
    Preclinical, Journal:  Acute ampakines increase voiding function and coordination in a rat model of SCI. (Pubmed Central) -  Mar 7, 2024   
    The 'low-impact' ampakine CX1739 (5, 10, or 15 mg/kg) or vehicle (2-hydroxypropyl-beta-cyclodextrin [HPCD]) was administered intravenously...We conclude that modulating AMPA receptor function using ampakines can rapidly improve bladder-voiding capability at subacute time points following contusion SCI. These results may provide a new and translatable method for therapeutic targeting of bladder dysfunction acutely after SCI.
  • ||||||||||  pentylenetetrazole (BTD-001) / Balance Therap
    Preclinical, Journal:  Knockdown of SIK3 in the CA1 Region can Reduce Seizure Susceptibility in Mice by Inhibiting Decreases in GABAR ?1 Expression. (Pubmed Central) -  Feb 27, 2024   
    In mice, knockdown of SIK3 reduced epilepsy susceptibility in a pentylenetetrazole (a GABA receptor antagonist, PTZ) acute kindling experiment and increased the expression of GABA receptor ?1. In conclusion, our results suggest that blockade or knockdown of SIK3 can inhibit epileptiform discharges and that SIK3 has the potential to be a novel target for epilepsy treatment.
  • ||||||||||  Fycompa (perampanel) / Eisai, Catalyst Pharma
    Review, Journal:  Understanding the role of AMPA receptors in autism: insights from circuit and synapse dysfunction. (Pubmed Central) -  Feb 14, 2024   
    Through the lens of the review, we will offer speculation on how neuromodulation may be used as a rational adjunct to therapy. Together, the present review seeks to synthesize the disparate considerations of circuit understanding, genetic etiology, and pharmacological modulation to understand the mechanistic interaction of this important and complex disorder.
  • ||||||||||  CX717 / RespireRx
    Preclinical, Journal:  Pattern sensitivity of ampakine-hypoxia interactions for evoking phrenic motor facilitation in anesthetized rat. (Pubmed Central) -  Jan 30, 2024   
    Ampakine CX717 (15 mg/kg iv) was given immediately before (n = 8), during (n = 8), or immediately after (n = 8) a 5-min hypoxic episode (arterial oxygen partial pressure 40-45 mmHg)...We conclude that the presentation order of ampakine and hypoxia impacts the magnitude of pMF, with ampakine pretreatment evoking the strongest response. Ampakine pretreatment may have value in the context of hypoxia-based neurorehabilitation strategies.
  • ||||||||||  Journal:  Thiazole Derivatives as Modulators of GluA2 AMPA Receptors: Potent Allosteric Effects and Neuroprotective Potential. (Pubmed Central) -  Dec 27, 2023   
    The abovementioned facts and the well-documented effects of further thiazole derivatives provide a strong foundation for future research endeavors to enhance tailored treatments for neurological disorders that rely heavily on GluA2 signaling. The present study elucidates the intricate association between thiazole derivatives and GluA2 receptors, providing valuable perspectives on the prospects of enhanced and specific therapeutic interventions for diverse neurological conditions.
  • ||||||||||  Journal:  5-Nitroisoxazoles in SAr Reactions: A Novel Chemo- and Regioselective Approach to Isoxazole-Based Bivalent Ligands of AMPA Receptors. (Pubmed Central) -  Nov 29, 2023   
    The best positive modulator potency was found for dimethyl 5,5'-(ethane-1,2-diylbis(sulfanediyl))bis(isoxazole-3-carboxylate), which potentiated the kainate-induced currents in a wide concentration range (10-10 M) with maximum potentiation of 77% at 10 M. The results were rationalized using molecular docking and molecular dynamics simulations of modulator complexes with the dimeric ligand-binding domain of the GluA2 AMPA receptor. The predicted physicochemical, ADMET, and PAINS properties confirmed that the AMPA receptor modulators based on the bis(isoxazole) scaffold may serve as potential lead compounds for the development of neuroprotective drugs.
  • ||||||||||  CX1739 / RespireRx
    Ampakines therapy improves voiding function and coordination following acute spinal cord injury (WCC Halls A-C) -  Nov 3, 2023 - Abstract #Neuroscience2023NEUROSCIENCE_4735;    
    Then we assessed the effects of vehicle (HPCD) and low impact ampakine (CX1739) over 30 minutes to investigate whether it could restore the voiding functions in SCI...Our findings suggest that modulating AMPA receptor function using ampakines can rapidly improve voiding capability at sub-acute time points following contusion SCI. These results may provide a new and translatable method for therapeutic targeting of bladder dysfunction acutely after SCI.
  • ||||||||||  CSF synapse marker changes in predementia Alzheimer (In-Person) -  Jul 6, 2023 - Abstract #AAIC2023AAIC_4183;    
    was most closely associated with worse memory recall. Lower NPTX2 was linked to poorer cognitive status within A+ groups, suggesting links to AMPAR dysregulation and excitotoxicity.
  • ||||||||||  Harnessing the endogenous regenerative potential of the injured spinal cord (CC: Theatre - 1st Flr) -  Jun 12, 2023 - Abstract #CNSF2023CNSF_322;    
    It can be expected that the newly synthesized compounds will also have pronounced effects on the glutamatergic system of the mammalian brain. We uncover an important mechanism by which AMPARs regulate the growth/phenotype of epNSPCs which can be targeted therapeutically to harness the regenerative potential of the injured spinal cord.
  • ||||||||||  Journal:  Modulatory mechanisms of TARP ?8-selective AMPA receptor therapeutics. (Pubmed Central) -  Mar 26, 2023   
    Unexpectedly, one ligand (JNJ-61432059) acts bifunctionally, negatively affecting GluA1 but exerting positive modulatory action on GluA2-containing AMPARs, in a TARP stoichiometry-dependent manner. These results further illuminate the action of TARPs, demonstrate the sensitive balance between positive and negative modulatory action, and provide a mechanistic platform for development of both positive and negative selective AMPAR modulators.
  • ||||||||||  Journal:  miR-124-3p mediates polygenic risk shared between schizophrenia and bipolar disorder. (Pubmed Central) -  Jan 20, 2023   
    In this issue of Neuron, Namkung et al. demonstrate that the microRNA miR-124-3p is associated with polygenic risk scores shared between schizophrenia and bipolar disorder and confers risk to behavioral alterations common to these two disorders through modulation of AMPA receptor neurotransmission.
  • ||||||||||  Journal:  Jujuboside B inhibits febrile seizure by modulating AMPA receptor activity. (Pubmed Central) -  Dec 23, 2022   
    demonstrate that the microRNA miR-124-3p is associated with polygenic risk scores shared between schizophrenia and bipolar disorder and confers risk to behavioral alterations common to these two disorders through modulation of AMPA receptor neurotransmission. JuB suppressed the excitability of hippocampal neurons by inhibiting the activity of AMPAR and reducing the intracellular free calcium, thereby relieving febrile seizures.
  • ||||||||||  hydroquinone / Generic mfg.
    Journal:  Novel Nanomolar Allosteric Modulators of AMPA Receptor of Bis(pyrimidine) Series: Synthesis, Biotesting and SAR Analysis. (Pubmed Central) -  Dec 12, 2022   
    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 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.
  • ||||||||||  Homeostatic release depression counteracts positive AMPA receptor modulation (SDCC Halls B-H) -  Oct 10, 2022 - Abstract #Neuroscience2022NEUROSCIENCE_10922;    
    Our data thus establish that presynaptic homeostatic plasticity at mammalian central synapses is bidirectional and can counteract specific receptor perturbations on the minute timescale. By extension, the PAM type-dependent nature of presynaptic release depression suggests receptor perturbation-specific homeostatic signaling.
  • ||||||||||  Arising evidence of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor modulation by tetraspanins (SDCC Halls B-H) -  Oct 10, 2022 - Abstract #Neuroscience2022NEUROSCIENCE_8044;    
    Further, colocalization of the GluA1(Q)flip subunit with Tspan7 was confirmed, while in case of co-expression with Tspan28, no colocalization was seen. Our electrophysiological data demonstrates that the investigated tetraspanins clearly modulate AMPA receptor amplitudes, while confocal microscopy results confirm colocalization of some tetraspanins and receptors in the plasma membrane.
  • ||||||||||  The role of AMPA receptor surface mobility in high-frequency short-term synaptic plasticity (SDCC Halls B-H) -  Oct 10, 2022 - Abstract #Neuroscience2022NEUROSCIENCE_5231;    
    We aim to determine exhaustively the respective contributions of presynaptic transmitter release and postsynaptic AMPAR biophysics and mobility in HF-STP and to identify physiological processes which act upon AMPAR kinetics and mobility to regulate HF-STP in the brain. Moreover, AMPAR cross-link is a promising tool to achieve cell-specific blockade of HF-STP that may allow the transition from modeling-based evidence of HF-STP roles in brain function to experimental evidence.
  • ||||||||||  sirolimus / Generic mfg.
    Journal:  Perspective on mTOR-dependent Protection in Status Epilepticus. (Pubmed Central) -  May 29, 2022   
    The perspective provides a novel scenario to understand refractory epilepsy and selfsustaining status epilepticus. It is expected to provide a beneficial outcome in patients suffering from temporal lobe epilepsy.
  • ||||||||||  CX717 / RespireRx
    Journal:  Ampakine-Hypoxia Induced Phrenic Motor Facilitation is Not Prevented by Intrathecal Methysergide. (Pubmed Central) -  May 14, 2022   
    After a stable baseline (BL) was established, intravenous (i.v.) ampakine (CX717, 15mg/kg) was followed by a single episode of hypoxia (arterial partial pressure of O = 42±9mmHg)...Intrathecal methysergide blocked pLTF (60 min post-AIH, phrenic burst amplitude = -2±31% BL, n=3), but intrathecal delivery of the DMSO vehicle did not (60 min: 94±28% BL, n=3). Collectively, these results do not support our hypothesis that phrenic motor facilitation induced by the pairing of ampakine with a single bout of hypoxia is dependent on serotonin receptor activation.
  • ||||||||||  CX717 / RespireRx
    Journal:  Ampakine CX717 Stimulates Diaphragm Activity following Mid-cervical Spinal Contusion Injury. (Pubmed Central) -  May 14, 2022   
    In summary, our data indicate that low dose, low impact ampakine treatment can increase diaphragm muscle output at an acute timepoint following mid-cervical contusion type injuries. These studies pave the path for future experiments to test if ampakine treatment can be combined with rehabilitation techniques to further enhance the therapeutic effect of ampakines in this injury model.