Pharmacology of ACEA-1416: A potent systemically active NMDA receptor glycine site antagonist

Victor I. Ilyin, Edward R. Whittemore, Minhtam Tran, Ke Zhong Shen, Sui Xiong Cai, Sunil M. Kher, John F.W. Keana, Eckard Weber, Richard M. Woodward

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


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 μM in oocytes, Kb = 1.6 μM in neurons). Oocyte assays indicated that ACEA-1416 is weak or inactive as an antagonist at NMDA receptor glutamate binding sites (Kb > 5.9 μM) and metabotropic glutamate receptors (Kb > 57 μM). 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 ~2 min and the biological half-time of protection was ~60 min. The ED50 measured at peak efficacy was ~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.

Original languageEnglish (US)
Pages (from-to)107-114
Number of pages8
JournalEuropean Journal of Pharmacology
Issue number2-3
StatePublished - Aug 29 1996


  • AMPA receptor antagonist
  • Anticonvulsant
  • NMDA receptor glycine site antagonist
  • Neuroprotection

ASJC Scopus subject areas

  • Pharmacology


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