The N-methyl-D-aspartate (NMDA) receptor/ion channel complex is the major excitatory neurotransmitter receptor in the brain. NMDA receptors are involved in numerous aspects of normal and abnormal brain function including neuronal excitation, brain plasticity, learning and memory, ischemic neuronal damage, epilepsy, nociception etc. Consequently, NMDA receptor antagonist drugs have potential as therapeutic agents in a variety of CNS disorders. Among the most important potential therapeutic target areas for these drugs is prevention of ischemic neuronal damage following stroke or global brain ischemia. However, the therapeutic exploitation of NMDA antagonists has been severely limited by the phencyclidine (PCP)-like behavioral side effects that are caused by the NMDA channel blockers such as MK801 or by the competitive NMDA antagonists such as CPP or CGS19755. In an attempt to create antagonists of the NMDA receptor that would lack adverse behavioral side effects, the principal investigators of this application have synthesized a series of novel quinoxalinedione analogs with high affinity, selectivity and antagonist efficacy at the glycine coagonist site of the NMDA receptor (the glycine/NMDA receptor). Preliminary work has shown that these novel glycine/NMDA antagonists--unlike previously available glycine site antagonists--are potently active in vivo after systemic administration. Furthermore, the novel glycine/NMDA antagonists were shown to be devoid of PCP-like behavioral side-effects in two animal models. In this application it is proposed to use the newly discovered glycine/NMDA antagonists as lead compounds for the synthesis of carefully selected analogs and to conduct detailed structure/activity studies in order to obtain insights into the likely pharmacophore which confers glycine/NMDA antagonist efficacy and selectivity to quinoxalinediones and related compounds. In addition, it is proposed to synthesize [3H]-labelled analogs of the most potent compounds as radioligands for binding assays. It is further proposed to create azido-derivatives as potential photoaffinity labels for the glycine binding site of the NMDA receptor. This work is expected to lead to the discovery of novel glycine/NMDA antagonists that are active in vivo activity after systemic administration and that lack PCP-like behavioral side-effects. Furthermore, this work is expected to result in the creation of novel probes for the biochemical characterization of glycine/NMDA receptors. The new antagonists should be invaluable tools to study and characterize glycine/NMDA receptors in vivo and in vitro.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Irvine
Schools of Medicine
United States
Zip Code
Lutfy, K; Doan, P; Nguyen, M et al. (1999) Effects of ACEA-1328, a NMDA receptor/glycine site antagonist, on U50,488H-induced antinociception and tolerance. Eur J Pharmacol 384:1-5
Lutfy, K; Doan, P; Weber, E (1999) ACEA-1328, a NMDA receptor/glycine site antagonist, acutely potentiates antinociception and chronically attenuates tolerance induced by morphine. Pharmacol Res 40:435-42
Lutfy, K; Doan, P; Nugyen, M et al. (1998) ACEA-1328, an NMDA receptor antagonist, increases the potency of morphine and U50,488H in the tail flick test in mice. Pharmacol Res 38:453-60
Lutfy, K; Weber, E (1998) Tolerance develops to the antinociceptive and motor impairing effects of ACEA-1416, a NMDA receptor antagonist, in the formalin and rotarod test in mice. Pharmacol Res 37:295-302
Guzikowski, A P; Whittemore, E R; Woodward, R M et al. (1997) Synthesis of racemic 6,7,8,9-tetrahydro-3-hydroxy-1H-1-benzazepine-2,5-diones as antagonists of N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. J Med Chem 40:2424-9
Cai, S X; Huang, J C; Espitia, S A et al. (1997) 5-(N-oxyaza)-7-substituted-1,4-dihydroquinoxaline-2,3-diones: novel, systemically active and broad spectrum antagonists for NMDA/glycine, AMPA, and kainate receptors. J Med Chem 40:3679-86
Cai, S X; Kher, S M; Zhou, Z L et al. (1997) Structure-activity relationships of alkyl- and alkoxy-substituted 1,4-dihydroquinoxaline-2,3-diones: potent and systemically active antagonists for the glycine site of the NMDA receptor. J Med Chem 40:730-8
Lutfy, K; Sadowski, B; Marek, P et al. (1996) Differential sensitivity of mice bred for stress-induced analgesia to morphine and ACEA-1011 in the formalin test. Pharmacol Biochem Behav 54:495-500
Guzikowski, A P; Cai, S X; Espitia, S A et al. (1996) Analogs of 3-hydroxy-1H-1-benzazepine-2,5-dione: structure-activity relationship at N-methyl-D-aspartate receptor glycine sites. J Med Chem 39:4643-53
Lutfy, K; Shen, K Z; Woodward, R M et al. (1996) Inhibition of morphine tolerance by NMDA receptor antagonists in the formalin test. Brain Res 731:171-81

Showing the most recent 10 out of 26 publications