RT Journal Article
SR Electronic
T1 Novel Structure Having Antagonist Actions at Both the Glycine Site of the <em>N</em>-Methyl-<span class="sc">d</span>-Aspartate Receptor and Neuronal Voltage-Sensitive Sodium Channels: Biochemical, Electrophysiological, and Behavioral Characterization
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 215
OP 227
VO 292
IS 1
A1 Lawrence D. Snell
A1 David J. Claffey
A1 James A. Ruth
A1 C. Fernando Valenzuela
A1 Rita Cardoso
A1 Zejun Wang
A1 Simon R. Levinson
A1 William A. Sather
A1 Anna V. Williamson
A1 Nan C. Ingersoll
A1 Larissa Ovchinnikova
A1 Sanjiv V. Bhave
A1 Paula L. Hoffman
A1 Boris Tabakoff
YR 2000
UL http://jpet.aspetjournals.org/content/292/1/215.abstract
AB A novel series of N-substituted 4-ureido-5,7-dichloro-quinolines were synthesized to contain pharmacophores directed at voltage-sensitive sodium channels (VSNaCs) and N-methyl-d-aspartate (NMDA) receptors. These compounds were shown to act in a use-dependent manner as antagonists of VSNaCs and to act as selective competitive antagonists at the strychnine-insensitive glycine recognition site of NMDA receptors. These agents had little or no effect on α-adrenergic receptors, other glutamate receptors, or sites other than the glycine site on the NMDA receptor, and did not block voltage-sensitive calcium channels in vitro. In vivo, the compounds were active in preventing or reducing the signs and symptoms of neurohyperexcitability and had anxiolytic properties. Unlike benzodiazepines, N-substituted 4-ureido-5,7-dichloro-quinolines showed little interaction with the sedative effects of ethanol, but were effective in controlling ethanol withdrawal seizures. The combined actions of these compounds on VSNaCs and NMDA receptors also impart properties to these compounds that are important for preventing and reducing excitotoxic neurodegeneration, but these compounds lack the undesirable side effects of other agents used for these purposes. The American Society for Pharmacology and Experimental Therapeutics