The glycine transporter-1 inhibitors NFPS and Org 24461: a pharmacological study

Hársing, László G.; Szikora, István; Szabó, Gitta; Schmidt, Éva; Sziray, N.; Sebban, C.; Tesolin-Decros, B; Mátyus, Péter; Egyed, András; Spedding, Michael; Lévay, György

doi:10.1016/s0091-3057(02)01078-x

Cited by 94 publications

(60 citation statements)

References 73 publications

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“…44,45,72,73 NFPS potentiates NMDA transmission in rat hippocampal slices, 74 in vivo hippocampus, 75 and in rat prefrontal cortex in vivo. 76 In behavioral screens, NFPS shows antipsychotic effectiveness profile as reflected in ability to reverse PCP-induced hyperactivity 44 and enhance prepulse inhibition of the acoustic startle reflex in DBA/2 mice, 75 as well as ability to stabilize in vivo dopamine release in PCP-treated rats. 77 Those studies strongly support the initial conjecture regarding the importance of glycine transport to NMDA regulation.…”

Section: Glycine Transport Inhibitorsmentioning

confidence: 98%

Inhibition of System A-mediated glycine transport in cortical synaptosomes by therapeutic concentrations of clozapine: implications for mechanisms of action

et al. 2004

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Clozapine is an atypical antipsychotic with particular efficacy in schizophrenia, possibly related to potentiation of brain N-methyl-D-aspartate receptor (NMDAR) -mediated neurotransmission. NMDARs are regulated in vivo by glycine, which is regulated in turn by glycine transporters. The present study investigates transport processes regulating glycine uptake into rat brain synaptosomes, along with effects of clozapine on synaptosomal glycine transport. Amino-acid uptake of amino acids was assessed in rat brain P2 synaptosomal preparations using a radiotransport assay. Synaptosomal glycine transport was inhibited by a series of amino acids and by the selective System A antagonist MeAIB (2-methylaminoisobutyric acid). Clozapine inhibited transport of both glycine and MeAIB, but not other amino acids, at concentrations associated with preferential clinical response (0.5-1 lg/ml). By contrast, other antipsychotics studied were ineffective. The novel glycine transport inhibitor Further, in meta-analytic studies, clozapine effect sizes are approximately double those of other agents. 4,5 Several theories have been proposed to account for the unique clinical effects of clozapine. These include preferential binding to serotonin (5-HT2A) receptors, 6 D4 selectivity, 7 or weak binding to D2 receptors with fast dissociation kinetics.8 However, these theories propose to account only for the decreased risk of extrapyramidal side effects associated with clozapine and other atypical antipsychotics, not for its preferential efficacy. Other newer atypicals, including risperidone and olanzapine, each share at least some of the above properties with clozapine. While these agents, like clozapine, have reduced risk of EPS, they do not appear to share clozapine's differential therapeutic efficacy, particularly against negative symptoms. Clozapine treatment typically produces trough plasma levels in the range of 0.2-1.2 mg/ml during therapeutic treatment, 9 with preferential response to clozapine being associated with plasma concentrations of approximately 0.5 mg/ml or greater in both cross-sectional 10 and longitudinal 11 studies. Two active metabolites of clozapine, desmethyl clozapine and clozapine-N-oxide, have also been described and

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Section: Glycine Transport Inhibitorsmentioning

confidence: 98%

Inhibition of System A-mediated glycine transport in cortical synaptosomes by therapeutic concentrations of clozapine: implications for mechanisms of action

et al. 2004

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“…[106][107][108] More recent studies have been performed with selective, high-affinity GTIs such as N[3-(4 0 -fluorophenyl)-3-(4 0 -phenylphenoxy)propyl]-sarcosine (NFPS) 109 or Org 24598. 110 As with GDA, high affinity GTIs have been found to reverse PCP-induced hyperactivity 111 and dopaminergic hyperreactivity 112 in rodents, and to potentiate hippocampal LTP 113 and NMDAR-dependent responses in prefrontal cortical neurons. 114 GTIs also reverse PPI abnormalities in DBA/2J mice 113 and rats with neonatal hippocampal lesions, 115 supporting a potential role of GTIs in treatment of schizophrenia.…”

Section: Glutamatergicmentioning

confidence: 99%

Glutamate as a therapeutic target in psychiatric disorders

2004

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Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Glutamatergic neurotransmission may be modulated at multiple levels, only a minority of which are currently being exploited for pharmaceutical development. Ionotropic receptors for glutamate are divided into N-methyl-D-aspartate receptor (NMDAR) and AMPA receptor subtypes. NMDAR have been implicated in the pathophysiology of schizophrenia. The glycine modulatory site of the NMDAR is currently a favored therapeutic target, with several modulatory agents currently undergoing clinical development. Of these, the full agonists glycine and D-serine have both shown to induce significant, large effect size reductions in persistent negative and cognitive symptoms when added to traditional or newer atypical antipsychotics in double-blind, placebo-controlled clinical studies. Glycine (GLYT1) and small neutral amino-acid (SNAT) transporters, which regulate glycine levels, represent additional targets for drug development, and may represent a site of action of clozapine. Brain transporters for D-serine have recently been described. Metabotropic glutamate receptors are positively (Group I) or negatively (Groups II and III) coupled to glutamatergic neurotransmission. Metabotropic modulators are currently under preclinical development for neuropsychiatric conditions, including schizophrenia, depression and anxiety disorders. Other conditions for which glutamate modulators may prove effective include stroke, epilepsy, Alzheimer disease and PTSD. Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Approximately 60% of neurons in the brain, including all cortical pyramidal neurons and thalamic relay neurons, utilize glutamate as their primary neurotransmitter. 1 As a result, virtually all thalamocortical, corticocortical and corticofugal neurotransmission in the brain is mediated by glutamate. Glutamate is released from presynaptic terminals in response to neuronal depolarization, and is recycled by excitatory amino acid (EAA) transporters located on both neurons and glia. 2 Within glia, glutamate is converted to glutamine and released into extracellular fluid from which it is reabsorbed into presynaptic terminals and converted back to glutamate via action of neuronal glutaminase. Up to 2/3 of brain energy metabolism is related to reuptake and recycling of glutamate. 3 As such, functional imaging modalities, such as PET and fMRI, indexing activity primarily of brain glutamatergic systems. 4 The exchange of glutamine from glia to neurons is accomplished by coordinated actions of two transport systems, systems N and A, both of which are members of sodium-dependent neutral amino acid (SNAT) family of transporters. 5 These transport systems also transport precursors for cysteine and glycine, which are precursors to glutathione synthesis. 6 As these transporters are electrogenic, glutamate transporters may also participate in cellular signaling. 7 As with glutamate and GABA transporters, these recycling systems may constitute interesti...

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“…We first employed the non-competitive GlyT1 inhibitor NFPS (22,23) to assess whether endogenously increased glycine promotes post-ischemic recovery of excitatory synaptic transmission. NFPS was used at concentrations up to 100 nM, which has been demonstrated to produce effective blockade of GlyT1, as evidenced by enhanced NMDA receptor-mediated excitatory synaptic currents (16,17).…”

Section: No Neuroprotective Effect Of Endogenous Glycine Under Blockamentioning

confidence: 99%

“…We then evaluated the neuroprotective effect of the competitive GlyT1 inhibitor sarcosine, which acts as a substrate (11,22). Although sarcosine (0.3 and 1 mM) alone did not elicit any apparent reduction of the fEPSP slope, 3 mM sarcosine reduced the fEPSP slope by 23.9 ± 10.0% (n = 5, P > 0.05) during 10 min before initiation of OGD (Fig.…”

Section: No Neuroprotective Effect Of Endogenous Glycine Under Blockamentioning

confidence: 99%

Neuroprotection via Strychnine-Sensitive Glycine Receptors During Post-ischemic Recovery of Excitatory Synaptic Transmission in the Hippocampus

2010

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Abstract. Recent evidence indicates that strychnine-sensitive glycine receptors are located in upper brain regions including the hippocampus. Because of excitatory effects of glycine via facilitation of NMDA-receptor function, however, the net effects of increased extracellular glycine on neuronal excitability in either physiological or pathophysiological conditions are mostly unclear. Here, we addressed the potential neuroprotective effect of either exogenous application of glycine and taurine, which are both strychnine-sensitive glycine-receptor agonists, or an endogenous increase of glycine via blockade of glycine transporter 1 (GlyT1) by assessing their ability to facilitate the functional recovery of field excitatory postsynaptic potentials (fEPSPs) after termination of brief oxygen/glucose deprivation (OGD) in the CA1 region in mouse hippocampal slices. Glycine and taurine promoted restoration of the fEPSPs after reperfusion, but this was never observed in the presence of strychnine. Interestingly, glycine and taurine appeared to generate neuroprotective effects only at their optimum concentration range. By contrast, blockade of GlyT1 by N -[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl]sarcosine or sarcosine did not elicit significant neuroprotection. These results suggest that activation of strychnine-sensitive glycine receptors potentially produces neuroprotection against metabolic stress such as OGD. However, GlyT1 inhibition is unlikely to elicit a sufficient increase in the extracellular level of glycine to generate neuroprotection.

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The glycine transporter-1 inhibitors NFPS and Org 24461: a pharmacological study

Cited by 94 publications

References 73 publications

Inhibition of System A-mediated glycine transport in cortical synaptosomes by therapeutic concentrations of clozapine: implications for mechanisms of action

Inhibition of System A-mediated glycine transport in cortical synaptosomes by therapeutic concentrations of clozapine: implications for mechanisms of action

Glutamate as a therapeutic target in psychiatric disorders

Neuroprotection via Strychnine-Sensitive Glycine Receptors During Post-ischemic Recovery of Excitatory Synaptic Transmission in the Hippocampus

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