Abstract：
:Phenytoin (DPH) is a clinically useful sodium (Na) channel blocker with efficacy against partial and generalized seizures. We have developed a novel hydantoin compound (HA) using comparative molecular field analysis (CoMFA) and evaluated its effects on hNa(v)1.2 channels. Both DPH and HA demonstrated affinity for resting (K(r)=13.9microM for HA, K(r)=464microM for DPH) and slow inactivated channels (K(I)=975nM for HA, K(I)=20.6microM for DPH). However, HA also exhibited an affinity for fast inactivated channels (K(I)=2.5microM) and shifted the V(1/2) for activation in the depolarizing direction. Furthermore, HA exhibited profound use dependent block at both 5 and 10Hz stimulation frequencies. In the 6Hz seizure model (32mA) HA had an ED(50) of 47.1mg/kg and a TD(50) of 131mg/kg (protective index (PI)=2.8). In comparison, the ED(50) for DPH was approximately 27.5mg/kg with a TD(50) of 35.6mg/kg (PI approximately 1.3). These findings provide evidence for the utility of CoMFA in the design of novel anticonvulsants and support the hypothesis that states selectivity plays an important role in achieving optimal protection with minimal side effects.
journal_name
Neuropharmacologyjournal_title
Neuropharmacologyauthors
Lenkowski PW,Batts TW,Smith MD,Ko SH,Jones PJ,Taylor CH,McCusker AK,Davis GC,Hartmann HA,White HS,Brown ML,Patel MKdoi
10.1016/j.neuropharm.2006.11.001subject
Has Abstractpub_date
2007-03-01 00:00:00pages
1044-54issue
3eissn
0028-3908issn
1873-7064pii
S0028-3908(06)00385-6journal_volume
52pub_type
杂志文章abstract：:The loss of synapses and a corresponding reduction in synaptic proteins are histopathological features of Alzheimer's disease that correlate strongly with dementia. Here we report that stable Aβ oligomers secreted by 7PA2 cells reduced the amount of synaptophysin, a protein used as an indicator of synapse density, in ...
journal_title：Neuropharmacology
pub_type： 杂志文章
doi：10.1016/j.neuropharm.2011.08.030
更新日期：2011-12-01 00:00:00
abstract：:Vortioxetine is a multimodal drug that blocks serotonin (5-HT) reuptake and directly modulates 5-HT receptors. The effects of subacute and long-term administration of vortioxetine on various aspects of catecholamine and glutamate systems were investigated using single-unit extracellular recordings and microiontophores...
journal_title：Neuropharmacology
pub_type： 杂志文章
doi：10.1016/j.neuropharm.2017.10.036
更新日期：2018-01-01 00:00:00
abstract：:The ventromedial nucleus of the hypothalamus (VMH) plays an important role in feeding and energy homeostasis. Electroconvulsive seizure (ECS) therapy is highly effective in the treatment of several psychiatric diseases, including depression, but may also have beneficial effects in other neurological diseases. Although...
journal_title：Neuropharmacology
pub_type： 杂志文章
doi：10.1016/j.neuropharm.2013.03.033
更新日期：2013-08-01 00:00:00
abstract：:Anxiety and depression are considered as stress-related disorders, which present considerable sex differentiation. In animal models of anxiety and depression sex differences have been described and linked to the sexually dimorphic hypothalamus-pituitary-adrenals (HPA) axis. The present study aimed to adjust corticoste...
journal_title：Neuropharmacology
pub_type： 杂志文章
doi：10.1016/j.neuropharm.2011.08.025
更新日期：2012-01-01 00:00:00
abstract：:γ-Aminobutyric acid B (GABAB) receptors and their ligands are postulated as potential therapeutic targets for the treatment of several brain disorders, including drug dependence. Over the past fifteen years positive allosteric modulators (PAMs) have emerged that enhance the effects of GABA at GABAB receptors and which...
journal_title：Neuropharmacology
pub_type： 杂志文章,评审
doi：10.1016/j.neuropharm.2014.06.016
更新日期：2015-01-01 00:00:00
abstract：:The in vivo striatal binding of [3H]SCH 23390, an antagonist of the D1 dopamine receptors, was investigated in mice submitted to pretreatment to either decrease (gammabutyrolactone 750 mg/kg, i.p.) or, increase (3,4-dihydroxyphenylalanine (L-DOPA) 200 mg/kg i.p. plus dexamphetamine 4 mg/kg, s.c.) dopaminergic transmis...
journal_title：Neuropharmacology
pub_type： 杂志文章
doi：10.1016/0028-3908(95)00187-5
更新日期：1996-03-01 00:00:00
abstract：:The effect of acute exposure to alcohols on ion current mediated by recombinant 5-HT3RA receptors transiently expressed in human embryonic kidney 293 cells was investigated. Cells transfected with 5-HT3RA cDNA expressed receptors with pharmacological and functional properties similar to those of native 5-HT3 receptors...
journal_title：Neuropharmacology
pub_type： 杂志文章
doi：10.1016/0028-3908(94)90131-7
更新日期：1994-12-01 00:00:00
abstract：:We investigated block of voltage-dependent Ca channels in freshly dissociated rat central and peripheral neurons by the synthetic peptide omega-Aga-IVA. Synthetic omega-Aga-IVA blocked approximately 90% of the high-threshold Ca current in cerebellar Purkinje neurons with an estimated Kd of approximately 1.5 nM, slight...
journal_title：Neuropharmacology
pub_type： 杂志文章
doi：10.1016/0028-3908(93)90010-z
更新日期：1993-11-01 00:00:00
abstract：:Administration of serotonin-enhancing drugs induces a distinctive behavioral syndrome in rodents. We previously reported that mice with a targeted disruption of the serotonin transporter (SERT) display some of these behaviors spontaneously, in the absence of drug. In the current studies, we assessed the drug-induced s...
journal_title：Neuropharmacology
pub_type： 杂志文章
doi：10.1016/j.neuropharm.2007.07.009
更新日期：2007-10-01 00:00:00
abstract：:Caretakers and clinicians alike have long recognized that individuals with autism spectrum disorder (ASD) can have altered sensory processing, which can contribute to its core symptoms. However, the pathobiology of sensory alterations in ASD is poorly understood. Here we examined nocifensive behavior in ASD mouse mode...
journal_title：Neuropharmacology
pub_type： 杂志文章
doi：10.1016/j.neuropharm.2016.09.013
更新日期：2016-12-01 00:00:00
abstract：:The impairment of social behaviors induced by social defeat stress exposure as juveniles is resistant to some antidepressants and an antipsychotic, although the underlying mechanisms and/or therapeutic target are not yet clear. In this study, we investigated the involvement of the glutamatergic neuronal system in the ...
journal_title：Neuropharmacology
pub_type： 杂志文章
doi：10.1016/j.neuropharm.2018.12.020
更新日期：2019-04-01 00:00:00
abstract：:The antagonist effects of the 4-carboxyphenylglycines: (S)-4-carboxy-3hydroxyphenylglycine (4C3HPG), (S)-4-carboxyphenylglycine (4CPG) and (+)-alpha-methyl-4-carboxyphenylglycine (M4CPG) were compared on functional responses of human metabotropic glutamate receptor (mGluR) subtypes mGluR1 alpha and mGluR5a. These rece...
journal_title：Neuropharmacology
pub_type： 杂志文章
doi：10.1016/0028-3908(95)00069-i
更新日期：1995-08-01 00:00:00
abstract：:An earlier finding that three systems were responsible for the uptake of gamma-aminobutyric acid by synaptosomes was corroborated. In addition, the existence of three uptake systems for RS-nipecotic acid and beta-alanine was demonstrated. We have called these systems high affinity, medium affinity and low affinity upt...
journal_title：Neuropharmacology
pub_type： 杂志文章
doi：10.1016/0028-3908(86)90183-8
更新日期：1986-05-01 00:00:00
abstract：:The present studies examined the relationship between protein kinase C (PKC) and L-type voltage-dependent calcium channels in modulating the release of neurotransmitter from K(+)-depolarized rat spinal cord synaptosomes. Activators of PKC, such as phorbol 12-myristate 13-acetate (PMA), mezerein and oleoyl acetylglycer...
journal_title：Neuropharmacology
pub_type： 杂志文章
doi：10.1016/0028-3908(92)90005-a
更新日期：1992-11-01 00:00:00
abstract：:Anti-emetic drugs such as the tachykinin NK(1) receptor antagonists are useful to control emesis induced by diverse challenges. Evidence suggests pungent capsaicin-like TRPV1 activators also have broad inhibitory anti-emetic activity. However, pungent compounds are associated with undesirable effects including adverse...
journal_title：Neuropharmacology
pub_type： 杂志文章
doi：10.1016/j.neuropharm.2009.10.002
更新日期：2010-02-01 00:00:00
abstract：:We previously reported that elevated pressure induces axonal swelling and facilitates the synthesis of the neurosteroid, allopregnanolone (AlloP), in the ex vivo rat retina. Exogenously applied AlloP attenuates the axonal swelling, suggesting that the neurosteroid plays a neuroprotective role against glaucomatous pres...
journal_title：Neuropharmacology
pub_type： 杂志文章
doi：10.1016/j.neuropharm.2016.09.001
更新日期：2016-12-01 00:00:00
abstract：:Rodents emit ultrasonic vocalizations (USVs) to communicate the presence of positive or negative emotional states and to coordinate social interactions. On this basis, USVs are increasingly being used as a behavioral readout in rodent studies of affect, motivation and social behavior. Notably, several investigations h...
journal_title：Neuropharmacology
pub_type： 杂志文章,评审
doi：10.1016/j.neuropharm.2018.11.008
更新日期：2019-11-15 00:00:00
abstract：:Cannabinoid CB2 receptors (CB2Rs) are emerging as important therapeutic targets in brain disorders that typically involve neurometabolic alterations. We here addressed the possible role of CB2Rs in the regulation of glucose uptake in the mouse brain. To that aim, we have undertaken 1) measurement of (3)H-deoxyglucose ...
journal_title：Neuropharmacology
pub_type： 杂志文章
doi：10.1016/j.neuropharm.2016.03.015
更新日期：2016-11-01 00:00:00
abstract：:The aim of the present study was to determine the influence of thyroid hormone, T3, on the regulation of hippocampal BDNF expression by 5-HT receptor agonists. Chronic T3 administration prior to treatment with the 5-HT(1A) agonist, 8-OH-DPAT, significantly decreased BDNF mRNA in the dentate gyrus region of the hippoca...
journal_title：Neuropharmacology
pub_type： 杂志文章
doi：10.1016/s0028-3908(00)00094-0
更新日期：2001-01-01 00:00:00
abstract：:In nonhuman primates, anxiety levels are typically assessed by observing social hierarchies or behavior in an intruder task. As measures of anxiety might influence performance on a particular cognitive task, it is important to analyze these measures in the same room as used for the cognitive task. As we use a playroom...
journal_title：Neuropharmacology
pub_type： 杂志文章
doi：10.1016/j.neuropharm.2011.08.014
更新日期：2012-01-01 00:00:00
abstract：:In experiments in which mice were placed with their forepaws over a 4 cm high horizontal bar, delta-9-tetrahydrocannabinol (THC; 10 mg/kg i.p.) delayed descent from the bar. This effect on descent latency was markedly enhanced by physostigmine (0.05 or 0.25 mg/kg s.c.) and oxotremorine (0.04 or 0.08 mg/kg s.c.), admin...
journal_title：Neuropharmacology
pub_type： 杂志文章
doi：10.1016/0028-3908(91)90044-c
更新日期：1991-01-01 00:00:00
abstract：:Participation of opiate, serotonergic and noradrenergic components in the antinociceptive action of intrathecally administered morphine was evaluated by measuring the ability of subcutaneously administered doses of naloxone, methysergide and phentolamine to alter analgesia. Morphine produced a dose-dependent elevation...
journal_title：Neuropharmacology
pub_type： 杂志文章
doi：10.1016/0028-3908(89)90116-0
更新日期：1989-10-01 00:00:00
abstract：:Although depression is a severe and life-threatening psychiatric illness, its pathogenesis still is essentially unknown. Recent studies highlighted the influence of environmental stress factors on an individual's genetic predisposition to develop mood disorders. In the present study, we employed a well-validated stres...
journal_title：Neuropharmacology
pub_type： 杂志文章
doi：10.1016/j.neuropharm.2010.12.012
更新日期：2011-06-01 00:00:00
abstract：:The relevance and property of studies related to stress effects on immune function are undisputable. All studies conducted on stress-immune relationships, however, provide from physical and/or psychological stressors. Indeed, as far as it is of our knowledge brain-innate immune responses were not analyzed after anxiog...
journal_title：Neuropharmacology
pub_type： 杂志文章
doi：10.1016/j.neuropharm.2007.09.011
更新日期：2008-02-01 00:00:00
abstract：:Thiamethoxam (TMX) is a second-generation neonicotinoid which is known to induce toxic effects on insects and mammalians. Recently, it has been proposed that TMX is a poor agonist of insect nicotinic acetylcholine receptors (nAChRs) on isolated cell bodies. Here, we have studied its effect on synaptic transmission. Ou...
journal_title：Neuropharmacology
pub_type： 杂志文章
doi：10.1016/j.neuropharm.2010.12.008
更新日期：2011-03-01 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：:Cannabidiol (CBD), a non-euphorigenic compound derived from Cannabis, shows promise for improving recovery following cerebral ischemia and has recently been shown effective for the treatment of childhood seizures caused by Dravet and Lennox-Gastaut syndromes. Given evidence for activity to mitigate effects of CNS insu...
journal_title：Neuropharmacology
pub_type： 杂志文章
doi：10.1016/j.neuropharm.2019.107716
更新日期：2019-11-01 00:00:00
abstract：:Depotentiation, the reversal of long-term potentiation (LTP), can be induced by activation of metabotropic glutamate receptors (mGluRs) or NMDA receptors (NMDARs). Although NMDAR-dependent depotentiation is due to a protein phosphatase-dependent erasure of LTP, the notion that mGluR-dependent depotentiation also invol...
journal_title：Neuropharmacology
pub_type： 杂志文章
doi：10.1016/j.neuropharm.2005.01.008
更新日期：2005-06-01 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 acute effects of simvastatin lactone (lipophilic) and simvastatin acid (hydrophilic) on transient focal ischemia were assessed using the isolated guinea pig brain maintained in vitro by arterial perfusion. This new model of cerebral ischemia allows the assessment of the very early phase of the ischemic process, wi...
journal_title：Neuropharmacology
pub_type： 杂志文章
doi：10.1016/j.neuropharm.2011.01.003
更新日期：2011-05-01 00:00:00
