Isoxazolopyridone derivatives as allosteric metabotropic glutamate receptor 7 antagonists

Nakamura, Masayuki; Kurihara, Hideki; Suzuki, Gentaroh; Mitsuya, Morihiro; Ohkubo, Mitsuru; Ohta, Hisashi

doi:10.1016/j.bmcl.2009.11.070

Cited by 35 publications

(31 citation statements)

References 15 publications

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“…This selective mode of action of XAP044 differs from the mGlu7 NAM MMPIP, which also inhibits the actions of AMN082 (28,29). Therefore, independent lines of evidence suggest that XAP044 is a selective and orthosteric-like antagonist that acts at a specific binding site located within the VFTD of mGlu7.…”

Section: Discussionmentioning

confidence: 98%

“…ADX71743 (26) was shown to have robust anxiolytic-like effects in the elevated plus-maze (EPM) and the marble burying test. In contrast, MMPIP (27)(28)(29) showed no effects in a battery of anxiety-like and depressionrelated tests but was active in spatial learning tasks. Like AMN082, both NAMs likely act via allosteric sites in more lipophilic domains rather than at the VFTD.…”

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confidence: 94%

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Blocking Metabotropic Glutamate Receptor Subtype 7 (mGlu7) via the Venus Flytrap Domain (VFTD) Inhibits Amygdala Plasticity, Stress, and Anxiety-related Behavior

Gee

Peterlik

Neuhäuser

et al. 2014

Journal of Biological Chemistry

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Background: Behavioral genetics identified mGlu7 as a key regulator of brain emotion circuits. Results: An mGlu7-selective, Venus flytrap domain (VFTD)-directed antagonist inhibits fear, synaptic plasticity, stress, and anxiety in rodents. Conclusion: Pharmacological blockers of mGlu7 may represent promising future anxiolytics and antidepressants in man. Significance: The VFTD region of class C GPCRs provides a promising target for computer-assisted drug design.

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 94%

Blocking Metabotropic Glutamate Receptor Subtype 7 (mGlu7) via the Venus Flytrap Domain (VFTD) Inhibits Amygdala Plasticity, Stress, and Anxiety-related Behavior

Gee

Peterlik

Neuhäuser

et al. 2014

Journal of Biological Chemistry

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“…Recent discovery of the systemically active negative allosteric modulator (NAM) of mGlu 7 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo [4,5-c]pyridin-4(5H)-one (MMPIP) with inverse agonist activity was another step toward uncovering the role of this receptor (Suzuki et al, 2007;Nakamura et al, 2010). However, when tested in vivo, MMPIP impaired nonspatial and spatial memory in the object recognition and in the radial arm maze tests, respectively, and reduced social interaction in rats, while having no effects in a battery of tests relevant for motor function, anxiety, depression, sensorimotor gating, nociception, and seizure threshold (Hikichi et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

ADX71743, a Potent and Selective Negative Allosteric Modulator of Metabotropic Glutamate Receptor 7: In Vitro and In Vivo Characterization

Kalinichev

Rouillier

Girard

et al. 2012

J Pharmacol Exp Ther

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Metabotropic glutamate receptor 7 (mGlu 7 ) has been suggested to be a promising novel target for treatment of a range of disorders, including anxiety, post-traumatic stress disorder, depression, drug abuse, and schizophrenia. Here we characterized a potent and selective mGlu 7 negative allosteric modulatorIn vitro, Schild plot analysis and reversibility tests at the target confirmed the NAM properties of the compound and attenuation of L-(1)-2-amino-4-phosphonobutyric acid-induced synaptic depression confirmed activity at the native receptor. The pharmacokinetic analysis of ADX71743 in mice and rats revealed that it is bioavailable after s.c. administration and is brain penetrant (cerebrospinal fluid concentration/ total plasma concentration ratio at C max 5 5.3%). In vivo, ADX71743 (50, 100, 150 mg/kg, s.c.) caused no impairment of locomotor activity in rats and mice or activity on rotarod in mice.ADX71743 had an anxiolytic-like profile in the marble burying and elevated plus maze tests, dose-dependently reducing the number of buried marbles and increasing open arm exploration, respectively. Whereas ADX71743 caused a small reduction in amphetamine-induced hyperactivity in mice, it was inactive in the mouse 2,5-dimethoxy-4-iodoamphetamineinduced head twitch and the rat conditioned avoidance response tests. In addition, the compound was inactive in the mouse forced swim test. These data suggest that ADX71743 is a suitable compound to help unravel the physiologic role of mGlu 7 and to better understand its implication in central nervous system diseases. Our in vivo tests using ADX71743, reported here, suggest that pharmacological inhibition of mGlu 7 is a valid approach for developing novel pharmacotherapies to treat anxiety disorders, but may not be suitable for treatment of depression or psychosis.

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“…Although functionally selective and context-dependent behavior of compounds introduces potential complexity into ligand development, it is anticipated that this phenomenon will provide exciting opportunities to tailor new drug therapy to specifically affect coupling of GPCRs to some signaling pathways but not others. Suzuki et al recently reported the discovery of the compound MMPIP as a highly selective NAM of the metabotropic glutamate receptor subtype 7 (mGluR7) that exhibits intrinsic inverse agonist activity (Suzuki et al, 2007;Nakamura et al, 2010). This compound represents a major breakthrough in that it is the first selective antagonist of mGluR7, a receptor that is believed to play critical roles in regulating excitatory synaptic transmission in many regions of the CNS (Pelkey et al, 2005;Ayala et al, 2008;de Rover et al, 2008).…”

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confidence: 99%

Context-Dependent Pharmacology Exhibited by Negative Allosteric Modulators of Metabotropic Glutamate Receptor 7

Niswender¹,

Johnson²,

Miller³

et al. 2009

Mol Pharmacol

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Phenotypic studies of mice lacking metabotropic glutamate receptor subtype 7 (mGluR7) suggest that antagonists of this receptor may be promising for the treatment of central nervous system disorders such as anxiety and depression. Suzuki et al. (J Pharmacol Exp Ther 323:147-156, 2007) recently reported the in vitro characterization of a novel mGluR7 antagonist called 6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[ 4,5-c]pyridin-4(5H)-one (MMPIP), which noncompetitively inhibited the activity of orthosteric and allosteric agonists at mGluR7. We describe that MMPIP acts as a noncompetitive antagonist in calcium mobilization assays in cells coexpressing mGluR7 and the promiscuous G protein G␣ 15 . Assessment of the activity of a small library of MMPIP-derived compounds using this assay reveals that, despite similar potencies, compounds exhibit differences in negative cooperativity for agonist-mediated calcium mobilization. Examination of the inhibitory activity of MMPIP and analogs using endogenous G i/o -coupled assay readouts indicates that the pharmacology of these ligands seems to be context-dependent, and MMPIP exhibits differences in negative cooperativity in certain cellular backgrounds. Electrophysiological studies reveal that, in contrast to the orthosteric antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxyclycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495), MMPIP is unable to block agonist-mediated responses at the Schaffer collateral-CA1 synapse, a location at which neurotransmission has been shown to be modulated by mGluR7 activity. Thus, MMPIP and related compounds differentially inhibit coupling of mGluR7 in different cellular backgrounds and may not antagonize the coupling of this receptor to native G i/o signaling pathways in all cellular contexts. The pharmacology of this compound represents a striking example of the potential for context-dependent blockade of receptor responses by negative allosteric modulators.The G protein-coupled receptors (GPCRs) play critical roles in regulating a broad range of signaling pathways within virtually every organ system (George et al., 2002) and are the targets of intense discovery efforts for new drug candidates. Despite this concentrated focus, selective ligands do not exist for the majority of these receptors (Howard et al., 2001). Many GPCRs interact with natural ligands based on complex or highly restricted chemical scaffolds (for example, amino acids, peptides, lipids, etc.) that are not well suited to optimization of selective small-molecule reagents. In addition, high conservation of the orthosteric sites of GPCR subfamilies presents challenges in developing high selectivity for a given receptor subtype. For these reasons, increasing interest has been placed on identifying compounds that interact with GPCRs at allosteric, rather than orthosteric, binding

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Isoxazolopyridone derivatives as allosteric metabotropic glutamate receptor 7 antagonists

Cited by 35 publications

References 15 publications

Blocking Metabotropic Glutamate Receptor Subtype 7 (mGlu7) via the Venus Flytrap Domain (VFTD) Inhibits Amygdala Plasticity, Stress, and Anxiety-related Behavior

Blocking Metabotropic Glutamate Receptor Subtype 7 (mGlu7) via the Venus Flytrap Domain (VFTD) Inhibits Amygdala Plasticity, Stress, and Anxiety-related Behavior

ADX71743, a Potent and Selective Negative Allosteric Modulator of Metabotropic Glutamate Receptor 7: In Vitro and In Vivo Characterization

Context-Dependent Pharmacology Exhibited by Negative Allosteric Modulators of Metabotropic Glutamate Receptor 7

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