title: Pharmacology of ACEA-1416: a potent systemically active NMDA receptor glycine site antagonist.
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 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.
authors.affiliation: Acea Pharmaceuticals Inc., Irvine, CA 92718, USA.
authors.forename: V I
authors.initials: VI
authors.lastname: Ilyin
authors.forename: E R
authors.initials: ER
authors.lastname: Whittemore
authors.forename: M
authors.initials: M
authors.lastname: Tran
authors.forename: K Z
authors.initials: KZ
authors.lastname: Shen
authors.forename: S X
authors.initials: SX
authors.lastname: Cai
authors.forename: S M
authors.initials: SM
authors.lastname: Kher
authors.forename: J F
authors.initials: JF
authors.lastname: Keana
authors.forename: E
authors.initials: E
authors.lastname: Weber
authors.forename: R M
authors.initials: RM
authors.lastname: Woodward
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005998:Glycine / Q000378:metabolism*; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: C104712:ACEA 1416; D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D005998:Glycine