Tricyclic Quinoxalinediones: 5,6-Dihydro-1H-pyrrolo[1,2,3-de]quinoxaline-2,3-diones and 6,7-Dihydro-1H,5H-pyrido[1,2,3-de]quinoxaline-2,3-diones as Potent Antagonists for the Glycine Binding Site of the NMDA Receptor

Nagata, Ryu; Tanno, Norihiko; Kodo, Toru; Ae, Nobuyuki; Yamaguchi, Hiroshi; Nishimura, T.; Antoku, Fujio; Tatsuno, Tohru; Kato, Tatsuya; Tanaka, Yasuhisa

doi:10.1021/jm00049a015

Cited by 73 publications

(38 citation statements)

References 6 publications

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“…Based upon these observations, much e¤ort has been devoted to developing new classes of drugs designed to block NMDA receptor activity but lacking the disturbing psychotomimetic side e¤ects. A promising approach in this respect has been the synthesis of novel NMDA / glycine site antagonists which not only display high a¦nity for the NMDA / glycine regulatory site at the NMDA receptor but also have been shown to be potent inhibitiors of various NMDA receptor-mediated functional responses in vitro (Leeson and Iversen 1994;Nagata et al 1994;Keana et al 1995;Kehne et al 1995;Woodward et al 1995;Priestley et al 1996).…”

Section: Introductionmentioning

confidence: 99%

“…The arrival of novel, systemically active NMDA / glycine antagonists is now rapidly changing the situation (Leeson and Iversen 1994;Nagata et al 1994;Keana et al 1995). Furthermore, there is evidence to suggest that the novel, systemically active, NMDA / glycine site antagonists possess anticonvulsant and neuroprotective properties (Leeson et al 1994;Bristow et al 1996b;Ilyin et al 1996;Kotlinska and Liljequist 1996).…”

Section: Introductionmentioning

confidence: 99%

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A characterization of anxiolytic-like actions induced by the novel NMDA/glycine site antagonist, L-701,324

Kotlińska¹,

Liljequist²

1998

Psychopharmacology

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The effects of the NMDA/glycine site antagonist, 7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2(1H)-quinolone (L-701,324), and the benzodiazepine receptor agonist, diazepam, were examined in the elevated plus-maze and in the Vogel's conflict test. Oral administration of L-701,324 caused a dose-dependent increase (2.5 and 5.0 mg/kg, -30 min) in the percent time spent in the open arms with no change in the total number of arm entries or in the percent entries into the open arms of the plus-maze. The same doses of L-701,324 increased punished responding in the Vogel's conflict test in a dose-dependent fashion, with no influence on unpunished drinking behavior. The anxiolytic-like effects of L-701,324 were obtained at doses which by themselves had no influence on the locomotor activity of the animals. Diazepam (2 mg/kg, i.p., -30 min) was slightly more effective than L-701,324 in the plus-maze situation, whereas the increase in punished drinking in the Vogel's test was of the same magnitude for both compounds. Our present results suggest that inhibition of NMDA receptor activity via a blockade of the NMDA/glycine-sensitive site at the NMDA receptor is accompanied by a reduction of anxiety-like behavior in both non-conditioned and conditioned conflict behavior situations.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A characterization of anxiolytic-like actions induced by the novel NMDA/glycine site antagonist, L-701,324

Kotlińska¹,

Liljequist²

1998

Psychopharmacology

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“…The synthesis of (R)-angustureine (1) begins with the preparation of (S)-β-amino ester 3 by enzymatic kinetic resolution of racemic 3. 4 The material thus obtained was subjected to a three-step annulation sequence to dihydropyridone (DHPD) triflate 5: acylation of secondary amine 3, Reformatsky-type cyclocondensation, and enol triflation (3+45) (Scheme 2). This annulation sequence is conveniently conducted without purification of intermediates to afford 5 in 72% overall yield.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of (–)-(R)-angustureine by formal alkynylation of a chiral ß-amino ester

Díaz¹,

Dudley²

2013

Proceedings of the 15th Brazilian Meeting on Organic Synthesis Proceedings

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“…The N4-C5 bridged derivatives were extensively studied, [274][275][276][277][278] but most of them showed to be more selective for the Gly/NMDA receptor site than the AMPA ones. For example, SM18400 (35, Fig.…”

Section: (Hetero)cyclic-fused Quinoxalinone Derivativesmentioning

confidence: 99%

“…276 The studies reported on this series of compounds have been useful in clarifying the selectivity requirements for the AMPA and Gly/NMDA receptors. [276][277][278] The tricyclic C3-N4 bridged compounds were designed starting from the structural requirements suggested by reported AMPA pharmacophore models 45,225,242 and with the aim of improving physicochemical properties that characterized most of the quinoxaline-2,3-dione derivatives. In fact, the low-water solubility was in part attributed to the presence of the 2,3-dione moiety.…”

Section: (Hetero)cyclic-fused Quinoxalinone Derivativesmentioning

confidence: 99%

Competitive AMPA receptor antagonists

Catarzi

Colotta

Varano

2006

Medicinal Research Reviews

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Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) where it is involved in the physiological regulation of different processes. It has been well established that excessive endogenous Glu is associated with many acute and chronic neurodegenerative disorders such as cerebral ischaemia, epilepsy, amiotrophic lateral sclerosis, Parkinson's, and Alzheimer's disease. These data have consequently added great impetus to the research in this field. In fact, many Glu receptor antagonists acting at the N-methyl-D-aspartic acid (NMDA), 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA), and/or kainic acid (KA) receptors have been developed as research tools and potential therapeutic agents. Ligands showing competitive antagonistic action at the AMPA type of Glu receptors were first reported in 1988, and the systemically active 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline (NBQX) was first shown to have useful therapeutic effects in animal models of neurological disease in 1990. Since then, the quinoxaline template has represented the backbone of various competitive AMPA receptor antagonists belonging to different classes which had been developed in order to increase potency, selectivity and water solubility, but also to prolong the "in vivo" action. Compounds that present better pharmacokinetic properties and less serious adverse effects with respect to the others previously developed are undergoing clinical evaluation. In the near future, the most important clinical application for the AMPA receptor antagonists will probably be as neuroprotectant in neurodegenerative diseases, such as epilepsy, for the treatment of patients not responding to current therapies. The present review reports the history of competitive AMPA receptor antagonists from 1988 up to today, providing a systematic coverage of both the open and patent literature.

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Tricyclic Quinoxalinediones: 5,6-Dihydro-1H-pyrrolo[1,2,3-de]quinoxaline-2,3-diones and 6,7-Dihydro-1H,5H-pyrido[1,2,3-de]quinoxaline-2,3-diones as Potent Antagonists for the Glycine Binding Site of the NMDA Receptor

Cited by 73 publications

References 6 publications

A characterization of anxiolytic-like actions induced by the novel NMDA/glycine site antagonist, L-701,324

A characterization of anxiolytic-like actions induced by the novel NMDA/glycine site antagonist, L-701,324

Synthesis of (–)-(R)-angustureine by formal alkynylation of a chiral ß-amino ester

Competitive AMPA receptor antagonists

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