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Excitatory amino acid receptor antagonists show potential for the treatment of ischemic stroke and head trauma. In search of novel antagonists, a series of alkyl- and alkoxyl-substituted 1, 4-dihydro-2,3-quinoxalinediones were synthesized and assayed for inhibition of glutamate receptors. We report on the pharmacological characterization of one such compound, 7-chloro-6-methyl-5-nitro-1,4-dihydro-2, 3-quinoxalinedione (ACEA-1416). Electrophysiological assays showed that ACEA-1416 is a potent antagonist of rat brain NMDA receptors expressed in Xenopus oocytes, and NMDA receptors expressed by cultured rat cortical neurons. Antagonism is via competitive inhibition at glycine co-agonist sites (Kb = 7.9 nM in oocytes, Kb = 11 nM in neurons). ACEA-1416 also antagonizes AMPA receptors, though potency is considerably lower (Kb = 3.5 microM in oocytes, Kb = 1.6 microM in neurons). Oocyte assays indicated that ACEA-1416 is weak or inactive as an antagonist at NMDA receptor glutamate binding sites (Kb > 5.9 microM) and metabotropic glutamate receptors (Kb > 57 microM). Many NMDA receptor glycine site antagonists show poor penetration of the blood-brain barrier. Systemic bioavailability of ACEA-1416 was assessed by measuring the ability of the compound to protect against electroshock-induced seizures in mice. Protective effects of ACEA-1416 had rapid onset following i.v. administration. Peak efficacy was at approximately 2 min and the biological half-time of protection was approximately 60 min. The ED50 measured at peak efficacy was approximately 1.5 mg/kg. Our results show that ACEA-1416 is a high potency systemically active NMDA receptor glycine site antagonist and a moderate potency AMPA receptor antagonist. Separate studies indicate that ACEA-1416 is efficacious as a neuroprotectant in a rat model of focal cerebral ischemia. Taken together, our results suggest that ACEA-1416 has potential for clinical development as a neuroprotectant.
V I Ilyin, and
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R M Woodward
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R M Woodward
November 1999,
European journal of pharmacology,
V I Ilyin, and
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R M Woodward
December 1996,
Brain research,
V I Ilyin, and
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November 1999,
Pharmacological research,
V I Ilyin, and
E R Whittemore, and
M Tran, and
K Z Shen, and
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J F Keana, and
E Weber, and
R M Woodward
March 1995,
Molecular pharmacology,
V I Ilyin, and
E R Whittemore, and
M Tran, and
K Z Shen, and
S X Cai, and
S M Kher, and
J F Keana, and
E Weber, and
R M Woodward
January 1995,
NIDA research monograph,
V I Ilyin, and
E R Whittemore, and
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J F Keana, and
E Weber, and
R M Woodward
December 2004,
Neuropharmacology,
V I Ilyin, and
E R Whittemore, and
M Tran, and
K Z Shen, and
S X Cai, and
S M Kher, and
J F Keana, and
E Weber, and
R M Woodward
January 1997,
Brain research,
V I Ilyin, and
E R Whittemore, and
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K Z Shen, and
S X Cai, and
S M Kher, and
J F Keana, and
E Weber, and
R M Woodward
January 1991,
Journal of neural transmission. General section,
V I Ilyin, and
E R Whittemore, and
M Tran, and
K Z Shen, and
S X Cai, and
S M Kher, and
J F Keana, and
E Weber, and
R M Woodward
April 1998,
Pharmacological research,
