Structure–activity relationships of novel non-competitive mGluR1 antagonists: A potential treatment for chronic pain

Owen, Dafydd R.; Dodd, Peter G.; Gayton, Simon; Greener, Ben S; Harbottle, Gareth W.; Mantell, Simon J.; Maw, Graham N.; Osborne, Simon A.; Rees, H.; Ringer, Tracy J.; Rodriguez-Lens, Margarita; Smith, G. F.

doi:10.1016/j.bmcl.2006.10.015

Cited by 17 publications

(11 citation statements)

References 10 publications

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“…The natural consequence of competitive antagonists, the structural similarity to the endogenous agonist glutamate, is the difficulty in making highly subtype selective glutamate antagonists, with unsurprising side effects on mGluR5, group II or Group III mGluRs [25]. The identification of nonglutamate binding mGluR1 allosteric modulators, such as BAY36-7620 and Riluzole, improves the chances of identifying mGluR subtype selective molecules with better drug-like properties [29]. BAY36-7620 is a potent, non-competitive mGluR1 antagonist, and inhibits >60% of mGlu1a receptor constitutive activity without displacement of the [ 3 H]quisqualate binding from the glutamate-binding pocket [30].…”

Section: Discussionmentioning

confidence: 99%

Anti-Cancer Effect of Metabotropic Glutamate Receptor 1 Inhibition in Human Glioma U87 Cells: Involvement of PI3K/Akt/mTOR Pathway

Zhang

Yuan

et al. 2015

Cell Physiol Biochem

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Background: Metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors that mediate neuronal excitability and synaptic plasticity in the central nervous system, and emerging evidence suggests a role of mGluRs in the biology of cancer. Previous studies showed that mGluR1 was a potential therapeutic target for the treatment of breast cancer and melanoma, but its role in human glioma has not been determined. Methods: In the present study, we investigated the effects of mGluR1 inhibition in human glioma U87 cells using specific targeted small interfering RNA (siRNA) or selective antagonists Riluzole and BAY36-7620. The anti-cancer effects of mGluR1 inhibition were measured by cell viability, lactate dehydrogenase (LDH) release, TUNEL staining, cell cycle assay, cell invasion and migration assays in vitro, and also examined in a U87 xenograft model in vivo. Results: Inhibition of mGluR1 significantly decreased the cell viability but increased the LDH release in a dose-dependent fashion in U87 cells. These effects were accompanied with the induction of caspase-dependent apoptosis and G0/G1 cell cycle arrest. In addition, the results of Matrigel invasion and cell tracking assays showed that inhibition of mGluR1 apparently attenuated cell invasion and migration in U87 cells. All these anti-cancer effects were ablated by the mGluR1 agonist L-quisqualic acid. The results of western blot analysis showed that mGluR1 inhibition overtly decreased the phosphorylation of PI3K, Akt, mTOR and P70S6K, indicating the mitigated activation of PI3K/Akt/mTOR pathway. Moreover, the anti-tumor activity of mGluR1 inhibition in vivo was also demonstrated in a U87 xenograft glioma model in athymic nude mice. Conclusion: The remarkable efficiency of mGluR1 inhibition to induce cell death in U87 cells may find therapeutic application for the treatment of glioma patients.

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Section: Discussionmentioning

confidence: 99%

Anti-Cancer Effect of Metabotropic Glutamate Receptor 1 Inhibition in Human Glioma U87 Cells: Involvement of PI3K/Akt/mTOR Pathway

Zhang

Yuan

et al. 2015

Cell Physiol Biochem

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“…Subsequently, several novel negative allosteric mGlu1 receptor modulators (Table 6) were described that in functional in vitro assays had high potencies with IC 50 values in the low nanomolar range: (3,4- (Lavreysen et al, 2004), 6-amino-N-cyclohexyl-N,3-dimethylthiazolo [3,2-a]benzimidazole-2-carboxamide hydrochloride (YM-298198) (Kohara et al, 2005) (Kohara et al, 2007), FTIDC (Suzuki et al, 2007a), 3-cyclohexyl-5-fluoro-6-methyl-7-(2-morpholin-4-ylethoxy)-4H-chromen-4-one (Fukuda et al, 2009) and compounds IX (Micheli et al, 2003) and X (Zheng et al, 2005) in Table 6. A number of additional negative allosteric mGlu1 receptor modulators (not shown in Table 6) have been described; their structures are given in the respective references (Mabire et al, 2005;Micheli et al, 2006;Di Fabio et al, 2007;Owen et al, 2007;Vanejevs et al, 2008;Sasikumar et al, 2009;Satoh et al, 2009). Some of these molecules showed good in vivo-activity, especially in models for chronic pain (see below).…”

Section: Allosteric Modulators Of the Mglu1 Receptor A Negative Allomentioning

confidence: 99%

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

2011

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Section: Chemistrymentioning

confidence: 99%

“…Apart from anti-microbial activity, literature search showed that compounds 1, 5, 6, 13, and 15 were previously evaluated as 5-HT3 receptor antagonists for the management of depression [14]. Compound 32 was evaluated as a G-protein-coupled metabotropic receptor (mGluR1) antagonist for the treatment of chronic pain [15]. Regarding antimycobacterial activity against Mtb H37Ra, we found that compounds with methylene bridge (N-benzyl derivatives; 15-31) in general had better activity than N-phenyl derivatives (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14).…”

Section: Chemistrymentioning

confidence: 99%

“…Based on the observed whole-cell antimycobacterial activity (Table 1), we chose compound 2 as a representative of the N-phenyl subseries (1-14, excl. 6) and compound 20 as a representative of the N-benzyl series (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). These prototypic compounds were docked into mycobacterial DprE1 (pdb id: 4P8N).…”

Section: In Vitro Cytotoxicitymentioning

confidence: 99%

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Synthesis, Biological Evaluation, and In Silico Modeling of N-Substituted Quinoxaline-2-Carboxamides

Bouz

Janďourek

et al. 2021

Pharmaceuticals

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Despite the established treatment regimens, tuberculosis remains an alarming threat to public health according to WHO. Novel agents are needed to overcome the increasing rate of resistance and perhaps achieve eradication. As part of our long-term research on pyrazine derived compounds, we prepared a series of their ortho fused derivatives, N-phenyl- and N-benzyl quinoxaline-2-carboxamides, and evaluated their in vitro antimycobacterial activity. In vitro activity against Mycobacterium tuberculosis H37Ra (represented by minimum inhibitory concentration, MIC) ranged between 3.91–500 µg/mL, with most compounds having moderate to good activities (MIC < 15.625 µg/mL). The majority of the active compounds belonged to the N-benzyl group. In addition to antimycobacterial activity assessment, final compounds were screened for their in vitro cytotoxicity. N-(naphthalen-1-ylmethyl)quinoxaline-2-carboxamide (compound 29) was identified as a potential antineoplastic agent with selective cytotoxicity against hepatic (HepG2), ovarian (SK-OV-3), and prostate (PC-3) cancer cells lines. Molecular docking showed that human DNA topoisomerase and vascular endothelial growth factor receptor could be potential targets for 29.

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Structure–activity relationships of novel non-competitive mGluR1 antagonists: A potential treatment for chronic pain

Cited by 17 publications

References 10 publications

Anti-Cancer Effect of Metabotropic Glutamate Receptor 1 Inhibition in Human Glioma U87 Cells: Involvement of PI3K/Akt/mTOR Pathway

Anti-Cancer Effect of Metabotropic Glutamate Receptor 1 Inhibition in Human Glioma U87 Cells: Involvement of PI3K/Akt/mTOR Pathway

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

Synthesis, Biological Evaluation, and In Silico Modeling of N-Substituted Quinoxaline-2-Carboxamides

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