PHARMACOLOGY OF ACEA-1416 - A POTENT SYSTEMICALLY ACTIVE NMDA RECEPTOR GLYCINE SITE ANTAGONIST

Excitatory amino acid receptor antagonists show potential for the trea tment of ischemic stroke and head trauma. In search of novel antagonis ts, a series of alkyl- and alkoxyl-substituted 1, 4-dihydro-2, 3-quino xalinediones were synthesized and assayed for inhibition of glutamate receptors. We report on the pharmacological characterization of one su ch compound, -6-methyl-5-nitro-1,4-dihydro-2,3-quinoxalinedione (ACEA- 1416). Electrophysiological assays showed that ACEA-1416 is a potent a ntagonist of rat brain NMDA receptors expressed in Xenopus oocytes, an d NMDA receptors expressed by cultured rat cortical neurons. Antagonis m is via competitive inhibition at glycine co-agonist sites (K-b = 7.9 nM in oocytes, K-b = 11 nM in neurons). ACEA-1416 also antagonizes AM PA receptors, though potency is considerably lower (K-b = 3.5 mu M in oocytes, K-b = 1.6 mu M in neurons). Oocyte assays indicated that ACEA -1416 is weak or inactive as an antagonist at NMDA receptor glutamate binding sites (K-b > 5.9 mu M) and metabotropic glutamate receptors (K -b > 57 mu M). Many NMDA receptor glycine site antagonists show poor p enetration of the blood-brain barrier, Systemic bioavailability of ACE A-1416 was assessed by measuring the ability of the compound to protec t against electroshock-induced seizures in mice. Protective effects of ACEA-1416 had rapid onset following i.v. administration. Peak efficac y was at similar to 2 min and the biological half-time of protection w as similar to 60 min. The ED(50) measured at peak efficacy was similar to 1.5 mg/kg. Our results show that ACEA-1416 is a high potency syste mically active NMDA receptor glycine site antagonist and a moderate po tency AMPA receptor antagonist, Separate studies indicate that ACEA-14 16 is efficacious as a neuroprotectant in a rat model of focal cerebra l ischemia. Taken together, our results suggest that ACEA-1416 has pot ential for clinical development as a neuroprotectant.