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Glutathione and Glutathione Derivatives: Possible Modulators of Ionotropic Glutamate Receptors
Published in Christopher A. Shaw, Glutathione in the Nervous System, 2018
Réka Janáky, Vince Varga, Zsolt Jenei, Pirjo Saransaari, Simo S. Oja
The ionotropic NMDA receptors are receptor-channel complexes with several interacting binding sites for ligands: Sites for agonists (e.g., NMDA, glutamate, and aspartate) and antagonists [e.g., 2-amino-5-phosphonovalerate (APV) and 3-(2-carboxypiperazine-4-yl) propyl-1-phosphonate (CPP)]. Because of the presence of two binding sites with different affinities for CPP (van Amsterdam et al. 1992), the existence of both agonist- and antagonist-preferring sites or conformational states has been suggested (Stone 1993).A glycine coactivatory site blocked by cyclic glycine analogs (e.g., l-hydroxy-3-amino-2-pyrrolidone, HA-966).An inside-channel Mg2+ site involved in the voltage-dependent block of the ionophore.A phencyclidine (PCP) site within the ion channel, which binds dissociative anesthetics with NMDA antagonistic properties—among them PCP itself, ketamine, and dizocilpine (MK-801)—in a use- and voltage-dependent manner.A modulatory site for Zn2+, which has a voltage-independent antagonistic action.Polyamine activatory sites, which are blocked by ifenprodil, a new neuroprotective agent.
Effects of Alcohol Abuse on Brain Neurochemistry
Published in John Brick, Handbook of the Medical Consequences of Alcohol and Drug Abuse, 2012
Several studies support the hypothesis that ethanol has a differential action on NMDA receptor isoforms. As mentioned earlier, ifenprodil most potently inhibits a subset of NMDA receptors that contain the NMDAR-2B subunit (Williams et al., 1993) and inhibits NMDA receptors that are sensitive to ethanol inhibition in cultured neurons (Lovinger, 1995) and in vivo (Yang et al., 1996). Reconstitution studies also suggest that ethanol has selective actions on particular subtypes of NMDA receptors. Several investigators have combined the NMDAR-1A variant with the four NMDAR-2 subunits in Xenopus oocytes or HEK-293 cells and examined the action of ethanol on responses to NMDA (Buller et al., 1995; Chu, Anantharam, and Treistman, 1995; Lovinger, 1995; Masood et al., 1994; Mirshahi and Woodward, 1995). Consistent with neuronal studies that suggest NMDAR-2B and ifenprodil predict potent inhibitory actions of ethanol, the ε2 subunit (mouse NMDAR-2B subunit) when expressed with the ζ1 (mouse NMDAR-1A variant) in Xenopus oocytes is significantly inhibited by concentrations of ethanol less than 25 mM (Masood et al., 1994). Higher concentrations of ethanol also inhibited ε1 (mouse NMDAR-2A subunit) combined with the ζ1, but concentrations as high as 100 mM had little or no effect on ε3 (mouse NMDAR-2C subunit) and ε4 (mouse NMDAR-2D subunit) combined with ζ1 (mouse NMDAR-1A subunit). Similar studies done by Buller et al. (1995) found both NMDAR-2A and NMDAR-2B in combination with NMDAR-1A to be the NMDA receptor isoforms most sensitive to inhibition by ethanol. All studies agree that the recombinant NMDA receptors containing either the NMDAR-2C or the NMDAR-2D subunits with the NMDAR-1A subunit are not sensitive to ethanol inhibition (Buller et al., 1995; Lovinger, 1995; Masood et al., 1994). Lovinger (1995) found that the NMDA receptor formed from NMDAR-1A and NMDAR-2A was inhibited by ethanol, however, when NMDAR-2B was added, the recombinant NMDA receptor was considerably more sensitive to ethanol inhibition of NMDA than the recombinant receptor containing only the NMDAR-2A subunit. In vivo, NMDA receptors in the cerebral cortex likely contain combinations of NMDAR-1, NMDAR-2A, and NMDAR-2B subunits (Sheng et al., 1994). Taken together, the findings suggest that NMDA receptors containing NMDAR-2B subunits, alone or in combination with NMDAR-2A subunits, are likely to make up the NMDA receptor isoforms most sensitive to ethanol inhibition whereas those containing NMDAR-2C or NMDAR-2D subunits are likely to be relatively insensitive to inhibition by ethanol.
New approved and emerging pharmacological approaches to alcohol use disorder: a review of clinical studies
Published in Expert Opinion on Pharmacotherapy, 2021
Kirsten C Morley, Christina J Perry, Joshua Watt, Tristan Hurzeler, Lorenzo Leggio, Andrew J Lawrence, Paul Haber
Ifenprodil is a neuroprotective agent that is prescribed to improve dizziness after brain infarction or hemorrhage in Japan. It is primarily an antagonist for the N-Methyl-d-aspartate (NMDA) glutamate receptor, particularly at the NR2B subunit [74], which is upregulated following chronic alcohol [75]. NMDA receptors have been implicated in the rewarding properties of alcohol [76]. Ifenprodil is also a G protein-activated inwardly rectifying potassium (GIRK) channel inhibitor (GIRK) that has been found to reduce preference for addictive substances in mice [77]. GIRK channels may play an important role in signaling that is influenced by alcohol. Ethanol directly opens GIRK channels [78], where the opening of GIRK channels hyperpolarizes the cell membrane to modulate neuronal excitability.
Emerging drugs in the treatment of chronic cough
Published in Expert Opinion on Emerging Drugs, 2023
Danica Brister, Mustafaa Wahab, Moaaz Rashad, Nermin Diab, Martin Kolb, Imran Satia
Ifenprodil is a novel NMDA receptor antagonist which has recently been investigated in patients with RCC secondary to idiopathic pulmonary fibrosis (IPF). Ifenprodil specifically blocks the NMDA-type subunit 2B (GluN2B) and is licensed in Japan for the treatment of vertigo. In an open label uncontrolled study of 20 patients with IPF, there was a 38% reduction in 24-h cough frequency at week 12 compared to baseline [85]. Data from a larger placebo-controlled randomized trial is needed for further development.
Sigma receptor ligands haloperidol and ifenprodil attenuate hypoxia induced dopamine release in rat striatum
Published in Neurological Research, 2022
Murat Gursoy, Zulfiye Gul, R. Levent Buyukuysal
A major deficiency in Na+/K+-ATPase activity induced by depletion in ATP by hypoxia is seen as an important mechanism in dopamine release induced by hypoxia [23,52]. Inhibition of the Na+/K+-ATPase represents a key step in the cascade of hypoxia-induced impairment of cellular energy metabolism, also impairs or may even reverse the neurotransmitter transporter systems [53,54] including dopamine uptake transporter under hypoxic or ischemic conditions [23,52]. Thus, it is one possibility that sigma ligands may restore the hypoxia-induced ATP depletion as previous reports of the protective effect of sigma ligands on ischemia-induced ATP depletion in rat retina [55]. However, 10 μM ifenprodil failed in protecting the slices against hypoxia-induced ATP depletion in our study. Because this concentration of ifenprodil fully reversed the enhanced dopamine output to control level, attenuation of hypoxia-induced dopamine output by ifenprodil may not be related to the restoration of tissue ATP level. Another possibility is that sigma ligands, like dopamine uptake inhibitors, bind to transport proteins and inhibit the dopamine release occurred by reversed operation of dopamine transporters. To test this possibility, we compared the effect of haloperidol, MK-801 and nomifensine on dopamine release induced by potent and selective inhibitor of Na+/K+-ATPase, ouabain. Nomifensine, decreased ouabain-induced dopamine output and sensitivity of ouabain-induced dopamine output dependent on the concentration of ouabain in the medium. Haloperidol, as much as nomifensine, decreased low concentration of ouabain-induced dopamine output to control level. As observed with nomifensine, its efficiency was also found to be dependent on the ouabain concentration in the medium (Figure 5)). In contrast to haloperidol and nomifensine, MK-801 has failed to decrease ouabain-induced dopamine output. These findings support the possibility that nomifensine and haloperidol probably share a similar mechanism in attenuating ouabain-induced dopamine depletions.