Radioligand Binding Properties and Pharmacological Characterization of 6-Amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-carboxamide (YM-298198), a High-Affinity, Selective, and Noncompetitive Antagonist of Metabotropic Glutamate Receptor Type 1

Kohara, Atsuyuki; Toya, Takashi; Tamura, Shinzo; Watabiki, Tomonari; Nagakura, Yukinori; Shitaka, Yoshitsugu; Hayashibe, S.; Kawabata, Sueo; Okada, Masamichi

doi:10.1124/jpet.105.087171

Cited by 79 publications

(67 citation statements)

References 30 publications

(26 reference statements)

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“…7B), indicating a good linear correlation (r 2 = 0.85). (8,30). The rank order of K i of the allosteric antagonists to mGluR1 in the present study is similar to that of their inhibitory potencies (IC 50 ) obtained from functional assays using the same cell line, as shown in Table 1.…”

Section: Correlation Between Receptor Occupancy and In Vivo Activitiesupporting

confidence: 68%

Correlation of Receptor Occupancy of Metabotropic Glutamate Receptor Subtype 1 (mGluR1) in Mouse Brain With In Vivo Activity of Allosteric mGluR1 Antagonists

et al. 2009

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Abstract. The aim of this study was to clarify the relationship between receptor occupancy and in vivo pharmacological activity of mGluR1 antagonists. The tritiated mGluR1-selective allosteric antagonist [ H]FTIDC revealed that the receptor occupancy level by FTIDC correlated well with FTIDC dosage and plasma concentration. Intracerebroventricular administration of (S)-3,5-dihydroxyphenylglycine is known to elicit face washing behavior that is mainly mediated by mGluR1. Inhibition of this behavioral change by FTIDC correlated with the receptor occupancy level of mGluR1 in the brain. A linear relationship between the receptor occupancy and in vivo activity was also demonstrated using structurally diverse mGluR1 antagonists. The receptor occupancy assays could help provide guidelines for selecting appropriate doses of allosteric mGluR1 antagonist for examining the function of mGluR1 in vivo.

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Section: Correlation Between Receptor Occupancy and In Vivo Activitiesupporting

confidence: 68%

Correlation of Receptor Occupancy of Metabotropic Glutamate Receptor Subtype 1 (mGluR1) in Mouse Brain With In Vivo Activity of Allosteric mGluR1 Antagonists

et al. 2009

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“…Secondly, these compounds may improve the selectivity for individual mGluRs as well as enhance the scope for chemical tractability (26). In this direction, a new, promising, selective non-competitive mGluR1 antagonist, YM-298198, is now available, which is water soluble, whose binding site is close to the CPCCOEt allosteric site and which was shown to be highly active in vivo even with oral administration to exert an analgesic effect in streptozotocin-induced hyperalgesic mice (27). Recently, the group of Namkoong (28) suggested that the interference at specific points within GluR1 signal transduction should inhibit melanoma cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

The non-competitive metabotropic glutamate receptor-1 antagonist CPCCOEt inhibits the in vitro growth of human melanoma

Haas¹,

Pfragner²,

Siegl³

et al. 2007

Oncol Rep

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Abstract. Five decades ago, the dicarboxylic amino acid glutamate became recognized as the major excitatory neurotransmitter in the central nervous system. In recent years, the expression of glutamate receptors was detected also in peripheral, non-neuronal tissues. Furthermore, it was found that glutamate stimulated the proliferation and migration of several peripheral tumor cells, and that glutamate receptor antagonists limited tumor growth. Most of these studies, however, used broad spectrum compounds and/or groupspecific antagonists. Here we report that a selective, noncompetitive metabotropic glutamate receptor-1 antagonist, CPCCOEt (7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester), significantly inhibited the proliferation and modified the morphology of two human melanoma cell lines. These effects were independent of the external glutamate level in the culture medium. In addition, CPCCOEt significantly enhanced the tumoricidal effects of cytostatic drugs. Thus, selective non-competitive metabotropic glutamate receptor antagonists may be used alone and/or with the synergistic effects of chemotherapy, thus enhancing existing therapies of melanoma and possibly other malignancies.

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“…From in vivo experiments, orally administered YM-298198 showed a significant analgesic effect in streptozotocininduced hyperalgesic mice (30 mg/kg) [138]. In 2006, in a series of tricycloaromatics, novel pyridothienopyrimidine derivatives were reported as mGlu1 receptor antagonists, such as 10, that had IC 50 values of <50 nM [139].…”

Section: Mglu1 Receptor Antagonistsmentioning

confidence: 99%

Metabotropic Glutamate Receptors: Potential Drug Targets for Psychiatric Disorders

Yasuhara¹

2010

TOMCJ

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Metabotropic glutamate receptors (mGlu receptors) have emerged as new therapeutic targets for psychiatric disorders, such as schizophrenia, depression and anxiety with their regulatory roles in glutamatergic transmissions. To date, several ligands selective for each mGlu receptor have been synthesized, and pharmacological significances of these ligands have been demonstrated in animal models. Among them, mGlu2/3 receptor agonists have been proven to be effective for treating schizophrenia and anxiety disorders in clinical studies, which may prove utilities of mGlu receptor ligands for the treatment of psychiatric disorders. This article reviews recent advances in development of each mGlu receptor ligands and their therapeutic potential.

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Radioligand Binding Properties and Pharmacological Characterization of 6-Amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-carboxamide (YM-298198), a High-Affinity, Selective, and Noncompetitive Antagonist of Metabotropic Glutamate Receptor Type 1

Cited by 79 publications

References 30 publications

Correlation of Receptor Occupancy of Metabotropic Glutamate Receptor Subtype 1 (mGluR1) in Mouse Brain With In Vivo Activity of Allosteric mGluR1 Antagonists

Correlation of Receptor Occupancy of Metabotropic Glutamate Receptor Subtype 1 (mGluR1) in Mouse Brain With In Vivo Activity of Allosteric mGluR1 Antagonists

The non-competitive metabotropic glutamate receptor-1 antagonist CPCCOEt inhibits the in vitro growth of human melanoma

Metabotropic Glutamate Receptors: Potential Drug Targets for Psychiatric Disorders

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