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QUINOXALINEDIONES: NON-NMDA RECEPTOR ANTAGONISTS AS POTENTIAL DPUG CANDIDATES Tage HonorS, Malcolm J. Sheardown, Erik ~. Nielsen, Poul Jacobsen, Novo Wor#isk CNS Division, DK-2860 Soeborg, ~enmark The recent appearance of the noe-NMDA antagonists DNQX and CNQX initiated detailed studies of non-NMDA receptors. Structure activity studies of analogs of DNQX and CNQX revealed NBQX which shows higher affinity and selectivity for ~(PA receptors as compared to calcium sensiti ve kainate receptors, NMDA receptors, alvcin receptors, and PCP receptors. NBQX antagonizes quisqualate and kainate induced °H-GABA release from cultured cortical interneurones equally well, whereas NBQX antagonism of depolarizations induced by quisqualate and kainate in rat cortical wedae resembles the bindin 9 selectivities. Furthermore, NBQX lowers the seizure treshold to kainate in mice, whereas compounds which enhance GABA neurotransmission increase the seizure tres- hold. These results sugaest that cortical GABA interneurones mainly contain ~P~ receptors, whereas neurones downstream the interneurones may contain calcium sensitive kainate receptors. The most striking pharmacological effect of NBQX is the ability to block delayed neuronal cell death in hippocampus CAt layer following global ischaemia induced by 5 min occlusion of the arteries in Mongolian gerbils, when s~ministered before or 30, 60, 120 or 480 min after the onset of occlusion.

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THE ROLE OF EXCITATORY AMINO ACID AGONISTS AND ANTAGONISTS IN COMPLEX BEHAVIORAL PROCESSES. J.M. Moerschbaecher, Louisiana State University Medical Center, New Orleans, LA 70112-1393 USA The effects of various NMDA receptor agonists and antagonists were evaluated in monkeys responding under operant procedures designed to evaluate drug effects on learning and memory. When administered alone, NMDA, across a wide range of doses, failed to enhance acquisition in monkeys responding under a repeated acquisition procedure. Rather, at high doses, NMDA produced decreases in overall response rates which were antagonized by CGS 19755 in a dose- dependent manner. NMDA also failed to enhance retention of a discrimination following either a l-hr or 24-hr delay. At higher doses, however, NMDA decreased response rate and produced amnestic effects as evidenced by a decrease in percent savings. The amnestic effects of NMDA were antagonized by CGS 19755 at doses lower than those required to antagonize the rate- decreasing effects. Noncompetitive antagonists such as phencyclidine and MK-801 disrupted both learning and memory. While both were active, the (+)-isomer of MK-801 was approximately ten times more potent than the (-) isomer in this regard. The effects of CGS 19755 were modulated by the presession administration time. At a short time (15 min) it functioned as an competitive antagonist while at longer times (2 hr) it mimicked the effects of the noncompetitive antagonists. Thus it would appear that modulation of the NMDA receptor complex by both agonists and antagonists can result in a disruption in complex behavioral processes. (Supported by USPHS Grants DA 03573 and DA 04775.)

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ANTI-ISCH~MIC POTeNtIAL OF THE POLYAMINE SITE ANT~CNIST SL 82.0715

B.Scatton, C.Carter, J.Benavides, Synthelabo Recherche (L.E.R.S.), Bagneux, France.

ABSTRACT NOT RECEIVED