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 journalArticle

27 Citations (Scopus)

Abstract

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
Volume310
Issue number2-3
DOIs
StatePublished - Aug 29 1996

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N-Methyl-D-Aspartate Receptors
Glycine
Pharmacology
Oocytes
AMPA Receptors
Glutamate Receptors
Neuroprotective Agents
Neurons
ACEA 1416
Electroshock
Excitatory Amino Acid Antagonists
Metabotropic Glutamate Receptors
Aptitude
Xenopus
Brain Ischemia
Blood-Brain Barrier
Craniocerebral Trauma
Biological Availability
Glutamic Acid
Seizures

Keywords

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

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

Pharmacology of ACEA-1416 : A potent systemically active NMDA receptor glycine site antagonist. / Ilyin, Victor I.; Whittemore, Edward R.; Tran, Minhtam; Shen, Ke-Zhong; Cai, Sui Xiong; Kher, Sunil M.; Keana, John F W; Weber, Eckard; Woodward, Richard M.

In: European Journal of Pharmacology, Vol. 310, No. 2-3, 29.08.1996, p. 107-114.

Research output: Contribution to journalArticle

Ilyin, VI, Whittemore, ER, Tran, M, Shen, K-Z, Cai, SX, Kher, SM, Keana, JFW, Weber, E & Woodward, RM 1996, 'Pharmacology of ACEA-1416: A potent systemically active NMDA receptor glycine site antagonist', European Journal of Pharmacology, vol. 310, no. 2-3, pp. 107-114. https://doi.org/10.1016/0014-2999(96)00370-6
Ilyin, Victor I. ; Whittemore, Edward R. ; Tran, Minhtam ; Shen, Ke-Zhong ; Cai, Sui Xiong ; Kher, Sunil M. ; Keana, John F W ; Weber, Eckard ; Woodward, Richard M. / Pharmacology of ACEA-1416 : A potent systemically active NMDA receptor glycine site antagonist. In: European Journal of Pharmacology. 1996 ; Vol. 310, No. 2-3. pp. 107-114.
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