Novel structure having antagonist actions at both the glycine site of the N-methyl-D-aspartate receptor and neuronal voltage-sensitive sodium channels: biochemical, electrophysiological, and behavioral characterization.
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 alpha-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.
Snell
L D
LD
Lohocla Research Corporation, University of Colorado School of Medicine, Denver, CO, USA.
Claffey
D J
DJ
Ruth
J A
JA
Valenzuela
C F
CF
Cardoso
R
R
Wang
Z
Z
Levinson
S R
SR
Sather
W A
WA
Williamson
A V
AV
Ingersoll
N C
NC
Ovchinnikova
L
L
Bhave
S V
SV
Hoffman
P L
PL
Tabakoff
B
B
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001259:Ataxia / Q000209:etiology; D001522:Behavior, Animal / Q000187:drug effects; D001665:Binding Sites; D001667:Binding, Competitive; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000633:toxicity; D005998:Glycine / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009474:Neurons / Q000187:drug effects; D009865:Oocytes / Q000378:metabolism; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D011485:Protein Binding; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects; D017470:Receptors, Glutamate / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012640:Seizures / Q000209:etiology; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000737:chemistry; D013016:Sound / Q000009:adverse effects; D013331:Strychnine / Q000494:pharmacology; D013375:Substance Withdrawal Syndrome / Q000209:etiology; D014981:Xenopus / Q000235:genetics
D014151:Anti-Anxiety Agents; C403081:N,N-(diphenyl)-4-ureido-5,7-dichloro-2-carboxyquinoline; D010671:Phenylurea Compounds; D011804:Quinolines; D011942:Receptors, Adrenergic, alpha; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D000431:Ethanol; D013331:Strychnine; D005998:Glycine