Effects of a novel metabotropic glutamate receptor 7 negative allosteric modulator, 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazonolo[4,5-c]pyridin-4(5H)-one (MMPIP), on the central nervous system in rodents

Hikichi, Hirohiko; Murai, Takeshi; Okuda, Suguru; Maehara, Shunsuke; Satow, Akio; Ise, Satoko; Nishino, Masaya; Suzuki, Gentaroh; Takehana, Hiroshi; Hata, Masahiko; Ohta, Hisashi

doi:10.1016/j.ejphar.2009.08.047

Cited by 41 publications

(36 citation statements)

References 43 publications

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“…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.…”

mentioning

confidence: 93%

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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mentioning

confidence: 93%

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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“…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). An extensive pharmacological study of MMPIP and close analogs revealed that these compounds show a context-dependent activity when expressed in recombinant cell lines, but were found inactive in a physiologic setup (Niswender 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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“…However, recently reported profound changes in GABAergic system in mGlu7 KO mice (Wieroń ska et al, 2010) may explain the antidepressantlike phenotype of mGlu7 knockouts and resolve that discrepancy. Moreover, the recent data demonstrating that pharmacological blockade of mGlu7 receptors by 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazonolo[4,5-c]pyridin-4(5H)-one (MMPIP) did not cause antidepressant effects (Hikichi et al, 2010) support the view that it is the stimulation of mGlu7 receptors that brings about antidepressant-like activity. The possibility that AMN082 may act via additional mechanisms not related to the stimulation of mGlu7 receptors also has to be considered.…”

Section: Discussionmentioning

confidence: 62%

The Antidepressant-Like Action of Metabotropic Glutamate 7 Receptor Agonist N,N′-Bis(Diphenylmethyl)-1,2-Ethanediamine (AMN082) Is Serotonin-Dependent

Pałucha-Poniewiera¹,

Brański²,

Lenda³

et al. 2010

J Pharmacol Exp Ther

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Behavioral studies show that modulation of the glutamatergic system might be an efficient way to achieve antidepressant activity. Among the group III metabotropic glutamate (mGlu) receptors, the mGlu7 receptor subtype seems to be the most promising target for potential antidepressants. It has been shown that a selective, allosteric mGlu7 receptor agonist, N,NЈ-bis (diphenylmethyl)-1,2-ethanediamine (AMN082), induced antidepressantlike action in behavioral tests in mice, although the mechanisms responsible for this action remained unknown. Here, we decided to investigate the possible role of the serotonergic system in the antidepressant-like activity of AMN082 in both the forced swim test (FST) in rats and the tail suspension test (TST) in mice. We found that AMN082 (1-10 mg/kg i.p.) induced a dose-dependent reduction in the immobility of rats and an increase in their swimming behavior, whereas there were not any changes in climbing behavior in the FST in rats. In the TST in mice we found that AMN082 (3 mg/kg i.p.) did not induce an antidepressant-like effect after depletion of serotonin (5-HT) with para-chlorophenylalanine. Moreover, we revealed that citalopram, but not reboxetine, when combined with AMN082 (all compounds used at low subeffective doses), induced a significant antidepressant-like effect in the TST. We also discovered that the 5-HT1A receptor antagonist N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridynyl) cyclohexane-carboxamide (WAY100635) (0.1 mg/kg s.c.), but not the 5-HT2A/2C receptor antagonist ritanserin (0.5 mg/kg i.p.), blocked the antidepressant-like action of AMN082. Altogether, the results of our studies show that the antidepressant-like action of the mGlu7 receptor-positive modulator AMN082 depends on the activation of the serotonergic system.

show abstract

Effects of a novel metabotropic glutamate receptor 7 negative allosteric modulator, 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazonolo[4,5-c]pyridin-4(5H)-one (MMPIP), on the central nervous system in rodents

Cited by 41 publications

References 43 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

The Antidepressant-Like Action of Metabotropic Glutamate 7 Receptor Agonist N,N′-Bis(Diphenylmethyl)-1,2-Ethanediamine (AMN082) Is Serotonin-Dependent

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