(3SR,4aRS,6RS,8aRS)-6-[2-(1H-Tetrazol-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid: a structurally novel, systemically active, competitive AMPA receptor antagonist

Ornstein, Paul L.; Mb, Arnold; Nk, Augenstein; Lodge, David; Jd, Leander; Dd, Schoepp

doi:10.1021/jm00066a016

Cited by 118 publications

(69 citation statements)

References 5 publications

(6 reference statements)

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“…62 GRIA4, upregulated in our schwannoma samples, is one of the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionate)-sensitive glutamate receptors; it could be regulated by AMPA agonists such as the drug tezampanel. 63 HOXC11, upregulated in our synovial sarcoma samples, is a marker of poor prognosis in patients with renal clear-cell carcinoma. 64 Treatment with the Src/Abl inhibitor dasatinib prevents recruitment of the HOXC11 transcription factor to S100β, an established biomarker of cutaneous melanoma progression.…”

Section: Therapeutic Targets In Human Soft Tissue Tumors Ae Sarver Et Almentioning

confidence: 82%

Identification, by systematic RNA sequencing, of novel candidate biomarkers and therapeutic targets in human soft tissue tumors

Sarver

Thayanithy

et al. 2015

Laboratory Investigation

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Human sarcomas comprise a heterogeneous group of more than 50 subtypes broadly classified into two groups: bone and soft tissue sarcomas. Such heterogeneity and their relative rarity have made them challenging targets for classification, biomarker identification, and development of improved treatment strategies. In this study, we used RNA sequencing to analyze 35 primary human tissue samples representing 13 different sarcoma subtypes, along with benign schwannoma, and normal bone and muscle tissues. For each sarcoma subtype, we detected unique messenger RNA (mRNA) expression signatures, which we further subjected to bioinformatic functional analysis, upstream regulatory analysis, and microRNA (miRNA) targeting analysis. We found that, for each sarcoma subtype, significantly upregulated genes and their deduced upstream regulators included not only previously implicated known players but also novel candidates not previously reported to be associated with sarcoma. For example, the schwannoma samples were characterized by high expression of not only the known associated proteins GFAP and GAP43 but also the novel player GJB6. Further, when we integrated our expression profiles with miRNA expression data from each sarcoma subtype, we were able to deduce potential key miRNA-gene regulator relationships for each. In the Ewing's sarcoma and fibromatosis samples, two sarcomas where miR-182-5p is significantly downregulated, multiple predicted targets were significantly upregulated, including HMCN1, NKX2-2, SCNN1G, and SOX2. In conclusion, despite the small number of samples per sarcoma subtype, we were able to identify key known players; concurrently, we discovered novel genes that may prove to be important in the molecular classification of sarcomas and in the development of novel treatments.

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Section: Therapeutic Targets In Human Soft Tissue Tumors Ae Sarver Et Almentioning

confidence: 82%

Identification, by systematic RNA sequencing, of novel candidate biomarkers and therapeutic targets in human soft tissue tumors

Sarver

Thayanithy

et al. 2015

Laboratory Investigation

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“…Vehicle injections for these compounds consisted of 0.01 N HCl. LY379268 (Monn et al, 1997) and LY293558 (Ornstein et al, 1993) were synthesized as described previously (Lilly Research Laboratories, Eli Lilly & Co.) and were dissolved in sterile saline.…”

Section: Methodsmentioning

confidence: 99%

The Group II Metabotropic Glutamate Receptor Agonist (−)-2-Oxa-4-aminobicyclo[3.1.0.]hexane-4,6-dicarboxylate (LY379268) and Clozapine Reverse Phencyclidine-Induced Behaviors in Monoamine-Depleted Rats

Swanson

Schoepp

2002

J Pharmacol Exp Ther

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Recent studies have indicated that the selective group II metabotropic glutamate (mGlu) receptor agonist (Ϫ)-2-oxa-4-aminobicyclo[3.1.0.]hexane-4,6-dicarboxylate (LY379268) shares common biochemical and pharmacological effects with the atypical antipsychotic clozapine. The present study aimed to further investigate these similarities (or differences) in monoamine-depleted animals by using the phencyclidine (PCP) model. Animals were pretreated 24 h before PCP administration with (i.p.) vehicle, ␣-methyl-DL-p-tyrosine methyl ester (␣-MPT; 400 mg/kg), or DL-pchlorophenyl-alanine methyl ester (PCPA; 300 mg/kg) injections. ␣-MPT and PCPA pretreatment significantly and selectively reduced catecholamine (dopamine and norepinepherine) or 5-hydroxytryptamine (5-HT, serotonin) and 5-hydroxyindoleacetic acid levels, respectively, in whole brain tissue. Both LY379268 and clozapine (s.c.) blocked PCP-evoked ambulatory activity and fine movements in control, ␣-MPT-, and PCPA-treated animals. In contrast, the typical antipsychotic haloperidol (s.c.) attenuated PCP behaviors in control and PCPA-pretreated animals, but was without effect in subjects pretreated with ␣-MPT. The ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/kainate-selective antagonist (3S,4aR,6R,8aR)-6-[2-(1(2)OH-tetrazole-6-yl)ethyl]decahydroisoquinoline-3-carboxylic acid (LY293558) attenuated locomotor activity in ␣-MPT-treated animals only, whereas the 5-HT 2A/2C -selective antagonist ketanserin was effective at reducing ambulations and fine movements in control and ␣-MPTtreated animals. Taken together, these data indicate an important role for glutamatergic and serotonergic mechanisms for PCP-evoked behaviors in catecholamine-depleted animals and suggest that like clozapine, LY379268 is more effective than typical antipsychotics in these models. This study further supports the potential use of group II mGlu agonists as novel therapeutic agents in the treatment of schizophrenia.

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“…Unlike NMDA antagonists, which are not active in global ischemia models, the AMPA antagonist NBQX is active in models of both focal and global cerebral ischemia. 102,103 The imidazolyl quinoxalinediones (23, Fig. 5…”

Section: Ampa Receptorsmentioning

confidence: 99%

Molecular targets for the rational design of antiepileptic drugs and related neuroprotective agents

Lin¹,

Kadaba²

1997

Med. Res. Rev.

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(3SR,4aRS,6RS,8aRS)-6-[2-(1H-Tetrazol-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid: a structurally novel, systemically active, competitive AMPA receptor antagonist

Cited by 118 publications

References 5 publications

Identification, by systematic RNA sequencing, of novel candidate biomarkers and therapeutic targets in human soft tissue tumors

Identification, by systematic RNA sequencing, of novel candidate biomarkers and therapeutic targets in human soft tissue tumors

The Group II Metabotropic Glutamate Receptor Agonist (−)-2-Oxa-4-aminobicyclo[3.1.0.]hexane-4,6-dicarboxylate (LY379268) and Clozapine Reverse Phencyclidine-Induced Behaviors in Monoamine-Depleted Rats

Molecular targets for the rational design of antiepileptic drugs and related neuroprotective agents

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