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Gabapentin (GBP) is a cyclic gamma-aminobutyric acid (GABA) analog and investigational antiepileptic drug which is effective in the treatment of a variety of human and experimental seizures. GBP's antiepileptic mechanism of action is not known. The present studies tested for effects of GBP on inhibitory (GABA and glycine) and excitatory(More)
Endogenous polyamines such as spermine and spermidine have multiple effects in the central nervous system and have been suggested to be neurotransmitters or neuromodulators. One effect of the polyamines is to regulate the activity of the N-methyl-D-aspartate receptor (NMDAR) channel subtype of glutamate receptor channels. The effects of polyamines on NMDAR(More)
Several polyamines have been shown to interact with a site on the N-methyl-D-aspartate (NMDA) receptor that regulates the binding of open channel blockers. Spermine (SP) and spermidine (SD), polyamine agonists, enhanced binding of open channel blockers, whereas arcaine (ARC), diethylenetriamine (DET), and putrescine (PUT), polyamine antagonists, reduced the(More)
Spermine potentiates the action of N-methyl-D-aspartate (NMDA) at micromolar concentrations but is less effective at millimolar concentrations. In cultured cortical neurons we demonstrate that spermine enhances NMDA receptor currents in a unique manner. At low concentrations (1-10 microM) spermine enhances NMDA receptor current by increasing channel opening(More)
Zonisamide is a novel anticonvulsant that prevents seizures in laboratory animals and in man. Zonisamide (3 micrograms/ml and above) blocked the sustained firing of action potentials induced by depolarizing steps of current injected across the membrane of intracellularly recorded spinal cord neurons. Responses to GABA and glutamate were not altered by(More)
The effects of diazepam, pentobarbital, phenytoin and pentylenetetrazol on paired-pulse inhibition were assessed in the intact rat hippocampus. Diazepam (4 mg/kg i.p.) and pentobarbital (15 mg/kg i.p.) increased inhibition over control levels, while phenytoin (15 mg/kg i.p.) and pentylenetetrazol (20 mg/kg i.p.) decreased inhibition from control levels. The(More)
Selective N-type voltage sensitive calcium channel (VSCC) blockers have shown efficacy in several animal models of stroke and pain. In the process of searching for small molecule N-type calcium channel blockers, we have identified a series of N-methyl-N-aralkyl-peptidylamines with potent functional activity at N-type VSCCs. The most active compound(More)
Recent in vitro and in vivo experiments have suggested that excitatory amino acid antagonists, particularly those active at the N-methyl-D-aspartate receptor subtype, are effective in ameliorating ischemic injury due to their antiexcitotoxic activity. However, these drugs are also potent and effective in vivo anticonvulsants. The present experiments(More)
A structure-based search and screen of our compound library identified N-(2-phenoxyethyl)-4-benzylpiperidine (8) as a novel N-methyl-D-aspartate (NMDA) receptor antagonist that has high selectivity for the NR1/2B subunit combination (IC(50) = 0.63 microM). We report on the optimization of this lead compound in terms of potency, side effect liability, and in(More)