Abstract
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.
Footnotes
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Send reprint requests to: Boris Tabakoff, Ph.D., Department of Pharmacology, Box C236, University of Colorado Health Sciences Center, 4200 E. Ninth Ave., Denver, CO. E-mail:Boris.Tabakoff{at}uchsc.edu
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↵1 This work was supported by Small Business Innovation Research Grant AA09930 and the Banbury Foundation.
- Abbreviations:
- NMDA
- N-methyl-d-aspartate
- VSNaC
- voltage-sensitive sodium channel
- CBZ
- carbamazepine
- CNS
- central nervous system
- DCUK
- N-substituted 4-ureido-5,7-dichloro-quinoline
- DCUKA
- N,N-(diphenyl)-4-ureido-5,7-dichloro-2-carboxy-quinoline
- DCUK-OMe
- N,N-(diphenyl)-4-ureido-5,7-dichloro-2-carboxyl methyl ester
- TLC
- thin layer chromatography
- DMSO
- dimethylsulfoxide
- BTX
- batrachiotoxin
- VSCC
- voltage-sensitive calcium channel
- 5,7-DCKA
- 5,7-dichlorokynurenic acid
- CGP39653
- d,l-(e)-2-amino-4-propyl-5-phosphono-3-pentenoic acid
- AMPA
- α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- GABA
- γ-aminobutyric acid
- DZP
- diazepam
- SR95531
- 2-(3′-carboxy-2′-propyl)-3-amino-6-p-methoxyphenylpyridazinium bromide
- MBS
- modified Barth's solution
- CMC
- carboxymethylcellulose
- AUC
- area under the curve
- CHO
- Chinese hamster ovary
- LORR
- loss of righting reflex
- Received June 28, 1999.
- Accepted September 13, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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