Abstract:
:The demonstrated functional interaction of metabotropic glutamate 5 (mGlu₅) receptors with N-methyl-d-aspartate (NMDA) receptors has prompted speculation that their activation may offer a potential treatment for aspects of schizophrenia. Development of selective mGlu₅ agonists has been difficult, but several different positive allosteric modulator (PAM) molecules have now been identified. This study describes two novel mGlu₅ PAMs, LSN2463359 (N-(1-methylethyl)-5-(pyridin-4-ylethynyl)pyridine-2-carboxamide) and LSN2814617 [(7S)-3-tert-butyl-7-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-A]pyridine], which are useful tools for this field of research. Both compounds are potent and selective potentiators of human and rat mGlu₅ receptors in vitro, displaying curve shift ratios of two to three fold in the concentration-response relationship to glutamate or the glutamate receptor agonist, DHPG, with no detectable intrinsic agonist properties. Both compounds displaced the mGlu₅ receptor antagonist radioligand, [³H]MPEP in vitro and, following oral administration reached brain concentrations sufficient to occupy hippocampal mGlu₅ receptors as measured in vivo by dose-dependent displacement from the hippocampus of intravenously administered MPEPy. In vivo EEG studies demonstrated that these mGlu₅ PAMs have marked wake-promoting properties but little in the way of rebound hypersomnolence. In contrast, the previously described mGlu₅ PAMs CDPPB and ADX47273 showed relatively poor evidence of in vivo target engagement in either receptor occupancy assays or EEG disturbance. Wake-promoting doses of LSN2463359 and LSN2814617 attenuated deficits in performance induced by the competitive NMDA receptor antagonist SDZ 220,581 in two tests of operant behaviour: the variable interval 30 s task and the DMTP task. These effects were lost if the dose of either compound extended into the range which disrupted performance in the baseline DMTP task. However, the improvements in response accuracy induced by the mGlu₅ potentiators in SDZ 220,581-treated rats were not delay-dependent and, therefore, perhaps more likely reflected optimization of general arousal than specific beneficial effects on discrete cognitive processes. The systematic profiling of LSN2463359 and LSN2814617 alongside other previously described molecules will help determine more precisely how mGlu₅ potentiator pharmacology might provide therapeutic benefit. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
journal_name
Neuropharmacologyjournal_title
Neuropharmacologyauthors
Gilmour G,Broad LM,Wafford KA,Britton T,Colvin EM,Fivush A,Gastambide F,Getman B,Heinz BA,McCarthy AP,Prieto L,Shanks E,Smith JW,Taboada L,Edgar DM,Tricklebank MDdoi
10.1016/j.neuropharm.2012.07.030subject
Has Abstractpub_date
2013-01-01 00:00:00pages
224-39eissn
0028-3908issn
1873-7064pii
S0028-3908(12)00366-8journal_volume
64pub_type
杂志文章abstract::The homotrimeric P2X3 receptor, one of the seven members of the ATP-gated P2X receptor family, plays a crucial role in sensory neurotransmission. P2X3 receptor antagonists have been identified as promising drugs to treat chronic cough and are suggested to offer pain relief in chronic pain such as neuropathic pain. Her...
journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/j.neuropharm.2019.107749
更新日期:2019-11-01 00:00:00
abstract::In this study, the role of CB₂r on aversive memory consolidation was further evaluated. Mice lacking CB₂r (CB2KO) and their corresponding littermates (WT) were exposed to the step-down inhibitory avoidance test (SDIA). MAP2, NF200 and synaptophysin (SYN)-immunoreactive fibers were studied in the hippocampus (HIP) of b...
journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/j.neuropharm.2013.05.034
更新日期:2013-10-01 00:00:00
abstract::Intrauterine inflammation is a major risk for offspring neurodevelopmental brain damage and may result in cognitive limitations and poor cognitive and perceptual outcomes. Pro-inflammatory cytokines, stimulated during inflammatory response, have a pleotrophic effect on neurons and glia cells. They act in a dose-depend...
journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/j.neuropharm.2004.12.023
更新日期:2005-05-01 00:00:00
abstract::Memory reactivation has been shown to open a time window for memory modulation. The majority of the methodological or pharmacological approaches target disruption of reconsolidation to weaken aversive memories. However, methods to improve appetitive memory persistence through reconsolidation or to reverse drug-induced...
journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/j.neuropharm.2018.08.015
更新日期:2018-10-01 00:00:00
abstract::Paeoniflorin (PF) is a major bioactive ingredient in Radix Paeonia alba roots that has low toxicity and has been shown to have neuroprotective effects. Our in vitro experiments suggested that PF affords a significant neuroprotective effect against MPP+-induced damage and apoptosis in PC12 cells through Bcl-2/Bax/caspa...
journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/j.neuropharm.2017.01.009
更新日期:2017-04-01 00:00:00
abstract::The effects of the anxiolytic drug chlordiazepoxide (CDZ) on general activity and anxiety-related behaviour of male and female Swiss-Webster mice were investigated in the triple test, which combines the open field (OF), elevated-plus maze (EPM) and the light-dark box (LDB). Mice were injected with saline or CDZ (1.0, ...
journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/j.neuropharm.2012.06.033
更新日期:2012-10-01 00:00:00
abstract::Reserpine (5 mg/kg s.c.) was given to rats kept under a reversed light-dark cycle and 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) determined in frontal cortex tissue and dialysate at various times after drug treatment. The decline and return of spontaneous locomotor activity was also measured. ...
journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/0028-3908(94)90088-4
更新日期:1994-03-01 00:00:00
abstract::The presence of ethanol, 100 microM, in the superfusate enhanced the spontaneous release of previously uptaken [3H]-dopamine from slices of rat corpus striatum, but produced a small inhibition of K+-stimulated release. The concomitant presence of picrotoxin, 10 microM, in the superfusate prevented the enhancement of s...
journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/0028-3908(83)90234-4
更新日期:1983-12-01 00:00:00
abstract::For a number of years it has been known that the CNS convulsant picrotoxin inhibits the GABA(A) receptor, an anion-selective member of the ligand-gated ion channel (LGIC) superfamily. PTX also inhibits other anion-selective LGIC members, such as GABA(C), glycine and glutamate-gated Cl(-) channels. In the present repor...
journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/s0028-3908(03)00032-7
更新日期:2003-03-01 00:00:00
abstract::Stimulus evoked neurotransmitter release requires that Na(+) channel-dependent nerve terminal depolarization be transduced into synaptic vesicle exocytosis. Inhaled anesthetics block presynaptic Na(+) channels and selectively inhibit glutamate over GABA release from isolated nerve terminals, indicating mechanistic dif...
journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/j.neuropharm.2011.05.013
更新日期:2011-09-01 00:00:00
abstract::In urethane-chloralose anesthetized, neuromuscularly blocked, ventilated rats, microinjection of NMDA (12 pmol) into the right fourth thoracic segment (T4) spinal intermediolateral nucleus (IML) immediately increased ipsilateral brown adipose tissue (BAT) sympathetic nerve activity (SNA; peak +492% of control), expire...
journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/j.neuropharm.2007.10.019
更新日期:2008-03-01 00:00:00
abstract::Hypotheses are scaffoldings erected in front of a building and then dismantled when the building is finished. They are indispensable for the workman; but you mustn't mistake the scaffolding for the building. Johann Wolfgang von Goethe. The neurogenesis hypothesis of affective disorders - in its simplest form - postula...
journal_title:Neuropharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.neuropharm.2011.09.003
更新日期:2012-01-01 00:00:00
abstract::Mutations in hundreds of genes contribute to cognitive and behavioral dysfunction associated with developmental brain disorders (DBDs). Due to the sheer number of risk factors available for study combined with the cost of developing new animal models, it remains an open question how genes should be prioritized for in-...
journal_title:Neuropharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.neuropharm.2015.07.029
更新日期:2016-01-01 00:00:00
abstract::3,4-methylenedioxypyrovalerone (MDPV) is a synthetic cathinone with cocaine-like properties. In a previous work, we exposed adolescent mice to MDPV, finding sensitization to cocaine effects, and a higher vulnerability to cocaine abuse in adulthood. Here we sought to determine if such MDPV schedule induces additional b...
journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/j.neuropharm.2018.10.005
更新日期:2019-01-01 00:00:00
abstract::Rat hearts were labelled with [3H]norepinephrine in vivo. Slices of ventricles were prepared, preincubated in Krebs-HCO3 medium (KRB), and then incubated in a Na+-deficient, choline+-Krebs HCO3 (Ch+-Ca2+). The choline+-Krebs HCO3 medium induced a delayed neurosecretion which could be inhibited by either one of the blo...
journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/0028-3908(85)90089-9
更新日期:1985-01-01 00:00:00
abstract::Glutamic acid is the major excitatory amino acid of the central nervous system which interacts with two receptor families, the ionotropic and metabotropic glutamate receptors. The metabotropic glutamate receptors (mGluRs) are coupled to G proteins and can be divided into three subgroups based on their sequence homolog...
journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/0028-3908(96)84622-3
更新日期:1996-05-01 00:00:00
abstract::Symptomatic temporal lobe epilepsy typically develops in three phases: brain damage --> epileptogenesis --> spontaneous seizures (epilepsy). The challenge is to prevent epileptogenesis after injury. We hypothesized that alleviation of damage by caspase inhibitors will reduce epileptogenesis or at least have disease-mo...
journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/s0028-3908(03)00115-1
更新日期:2003-06-01 00:00:00
abstract::mGlu7 receptors are coupled to Gi/Go-proteins and activate multiple transduction pathways, including inhibition of adenylyl cyclase activity and stimulation of ERK1/2 and JNK pathways. mGlu7 receptors play an important role in cognition and emotion and are involved in stress-related disorders such as anxiety and depre...
journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/j.neuropharm.2013.10.013
更新日期:2014-02-01 00:00:00
abstract::Mechanisms underlying stress-induced depression and antidepressant drug action were shown to involve alterations in serotonergic (5-HT) neurotransmission and expression of genes coding for proteins associated with neurotrophic signaling pathways and cell-survival in the hippocampus and cortex. Expression of these gene...
journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/j.neuropharm.2011.06.016
更新日期:2012-01-01 00:00:00
abstract::The effects of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an alkylating agent producing irreversible blockade of various membrane bound receptors in brain, were investigated on four different types of serotonin receptors, 5-HT1A, 5-HT1B, 5-HT2A and 5-HT3, in various brain regions in the rat. In addition, t...
journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/0028-3908(94)90072-8
更新日期:1994-03-01 00:00:00
abstract::Hippocampal Long-Term Potentiation (LTP) is facilitated by BDNF, through the activation of tropomyosin-related kinase B (TrkB) receptors. However, an influence of BDNF upon Long-Term Depression (LTD) was also shown. The present work aimed to further evaluate the effect of BDNF and TrkB receptors upon CA1 hippocampal L...
journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/j.neuropharm.2013.12.010
更新日期:2014-04-01 00:00:00
abstract::Clinical neuropathologic studies suggest that the selective vulnerability of hippocampal CA1 pyramidal projection neurons plays a key role in the onset of cognitive impairment during the early phases of Alzheimer's disease (AD). Disruption of this neuronal population likely affects hippocampal pre- and postsynaptic ef...
journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/j.neuropharm.2013.10.018
更新日期:2014-04-01 00:00:00
abstract::ɣ-aminobutyric-acid (GABA) functions as the principal inhibitory neurotransmitter in the central nervous system. Imbalances in GABAergic neurotransmission are involved in the pathophysiology of various neurological diseases such as epilepsy, Alzheimer's disease and stroke. GABA transporters (GATs) facilitate the termi...
journal_title:Neuropharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.neuropharm.2019.05.021
更新日期:2019-12-15 00:00:00
abstract::Of the ionotropic glutamatergic receptors, the NMDA receptor is clearly implicated in the acute and chronic effects of ethanol; however, the role of the AMPA receptor in mediating the effects of ethanol in vivo is as yet unclear. Using mice deficient in the AMPA receptor subunit GluR1 (GluR1-/- mice), we investigated ...
journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/s0028-3908(03)00174-6
更新日期:2003-09-01 00:00:00
abstract::The activity of tianeptine (2.5 and 5.0 mg/kg twice daily, i.p.) and of sertraline (5.0 mg/kg, twice daily, i.p.) were assessed in three animal models of depression. In the Behavioural Despair Test, acute treatment with sertraline or tianeptine (5.0 mg/kg) significantly reduced the immobility time. In the olfactory bu...
journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/0028-3908(94)90160-0
更新日期:1994-08-01 00:00:00
abstract::The incretins glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) are growth factors that have shown neuroprotective effects in animal models of Parkinson's and Alzheimer's disease. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in a clinical trial in Parkinson...
journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/j.neuropharm.2017.02.013
更新日期:2017-05-01 00:00:00
abstract::Ketogenesis is a metabolic process wherein ketone bodies are produced from the breakdown of fatty acids. In humans, fatty acid catabolism results in the production of acetyl-CoA which can then be used to synthesize three ketone bodies: acetoacetate, acetone, and β-hydroxybutyrate. Ketogenesis occurs at a higher rate i...
journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/j.neuropharm.2018.12.013
更新日期:2019-04-01 00:00:00
abstract::T-type (Cav3) calcium channels play important roles in neuronal excitability, both in normal and pathological activities of the brain. In particular, they contribute to hyper-excitability disorders such as epilepsy. Here we have characterized the anticonvulsant properties of TTA-A2, a selective T-type channel blocker,...
journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/j.neuropharm.2015.09.032
更新日期:2016-02-01 00:00:00
abstract::Cocaine induces neuroinflammatory response and interleukin-1 beta (IL1β) is suggested a final effector for many cocaine-induced inflammatory signals. Recently, the chemokine fractalkine (CX3CL1) has been reported to regulate hippocampus-dependent neuroinflammation and synaptic plasticity via CX3C-receptor 1 (CX3CR1), ...
journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/j.neuropharm.2019.107840
更新日期:2020-01-01 00:00:00
abstract::Valid animal models of psychopathology need to include behavioural readouts informed by human findings. In the probabilistic reversal learning (PRL) task, human subjects are confronted with serial reversal of the contingency between two operant stimuli and reward/punishment and, superimposed on this, a low probability...
journal_title:Neuropharmacology
pub_type: 杂志文章
doi:10.1016/j.neuropharm.2012.07.025
更新日期:2012-11-01 00:00:00