TY - JOUR
T1 - Pharmacology of ACEA-1416
T2 - A potent systemically active NMDA receptor glycine site antagonist
AU - Ilyin, Victor I.
AU - Whittemore, Edward R.
AU - Tran, Minhtam
AU - Shen, Ke Zhong
AU - Cai, Sui Xiong
AU - Kher, Sunil M.
AU - Keana, John F.W.
AU - Weber, Eckard
AU - Woodward, Richard M.
N1 - Funding Information:
J.F.W.K. and E.W. were supported in part by grant ROI DA 06726 from the National Institute of Drug Abuse. We thank Dr Z. Xu for technical assistance in the animal studies and Dr Yan Ni and Dr Ricardo Miledi (University of California Irvine) for the generous gift of rat brain poly(A+)RNA used in this study.
PY - 1996/8/29
Y1 - 1996/8/29
N2 - 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.
AB - 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.
KW - AMPA receptor antagonist
KW - Anticonvulsant
KW - NMDA receptor glycine site antagonist
KW - Neuroprotection
UR - http://www.scopus.com/inward/record.url?scp=0030605957&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0030605957&partnerID=8YFLogxK
U2 - 10.1016/0014-2999(96)00370-6
DO - 10.1016/0014-2999(96)00370-6
M3 - Article
C2 - 8884205
AN - SCOPUS:0030605957
SN - 0014-2999
VL - 310
SP - 107
EP - 114
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 2-3
ER -