Abstract |
5-Chloro-7-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (ACEA-1011) has analgesic properties in animal models of tonic pain. To investigate the mechanisms underlying this effect we used electrical recording techniques to characterize the in vitro pharmacology of ACEA-1011 at mammalian glutamate receptors. Two preparations were used: Xenopus oocytes expressing rat brain receptors and cultured rat cortical neurons. Results showed that ACEA-1011 is a competitive antagonist at NMDA receptor glycine sites. Apparent antagonist affinities (Kb values) were 0.4 to 0.8 microM in oocytes and approximately 0.6 microM in neurons. IC50 values for ACEA-1011 against four binary subunit combinations of cloned rat NMDA receptors (NR1A/NR2A, 2B, 2C or 2D) ranged from 0.4 to 8 microM (1 microM glycine). The 20-fold variation in sensitivity was due to a combination of subunit-dependent differences in glycine and antagonist affinities; EC50 values for glycine ranged between 0.08 to 0.8 microM and Kb values for ACEA-1011 between 0.2 to 0.8 microM. In addition, ACEA-1011 inhibited AMPA-preferring non- NMDA receptors by competitive antagonism at glutamate binding sites. Kb values were 4 to 9 microM in oocytes and 9 to 10 microM in neurons. The ED50 for ACEA-1011 in a mouse maximum electroshock-induced seizure model was approximately 12 mg/kg i.v.. Our results indicate that ACEA-1011 is a systemically active broad selectivity ionotropic glutamate receptor antagonist.
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Authors | R M Woodward, J E Huettner, M Tran, J Guastella, J F Keana, E Weber |
Journal | The Journal of pharmacology and experimental therapeutics
(J Pharmacol Exp Ther)
Vol. 275
Issue 3
Pg. 1209-18
(Dec 1995)
ISSN: 0022-3565 [Print] United States |
PMID | 8531083
(Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Analgesics
- Anticonvulsants
- Excitatory Amino Acid Antagonists
- Quinoxalines
- RNA, Messenger
- Receptors, Glutamate
- ACEA 1011
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Topics |
- Analgesics
(pharmacology)
- Animals
- Anticonvulsants
(pharmacology)
- Brain
(drug effects, metabolism, physiology)
- Cells, Cultured
- Cloning, Molecular
- Excitatory Amino Acid Antagonists
(pharmacology)
- Mice
- Neurons
(physiology)
- Quinoxalines
(pharmacology)
- RNA, Messenger
(metabolism)
- Rats
- Receptors, Glutamate
(metabolism)
- Seizures
(physiopathology, prevention & control)
- Xenopus laevis
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