Metabotropic Glutamate Receptor Subtype 5 Antagonists MPEP and MTEP

Lea, Paul M.; Faden, Alan I.

doi:10.1111/j.1527-3458.2006.00149.x

Cited by 147 publications

(114 citation statements)

References 214 publications

(265 reference statements)

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“…Thus, blocking I-LTD induction provides a means to block cocaineinduced aberrant synaptic plasticity and addictive behavior. Consistent with this idea, growing evidence suggests that CB 1 receptor and mGluR5 antagonists have considerable therapeutic potential in drug addiction (Lea and Faden, 2006;Maldonado et al, 2006 Ϫ/Ϫ mice do not self-administer cocaine (Chiamulera et al, 2001) and mGluR5 antagonist MPEP decreases cocaine self-administration in rats and monkeys (Lee et al, 2005;Paterson and Markou, 2005). These remarkable results suggest that CB 1 receptors and mGluR5 play an important role in cocaine addiction.…”

Section: The Implication Of I-ltd In Cocaine-seeking Behaviorsupporting

confidence: 58%

Endocannabinoid Signaling Mediates Cocaine-Induced Inhibitory Synaptic Plasticity in Midbrain Dopamine Neurons

Pan¹,

Hillard²,

Liu³

2008

J. Neurosci.

127

151

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Drugs that increase GABA levels in the brain reduce cocaine seeking in rodents and humans, suggesting that GABAergic inhibition regulates cocaine-seeking behavior. We previously reported that repeated cocaine exposure in vivo facilitates long-term potentiation by reducing the strength of GABAergic inhibition in dopamine neurons of the ventral tegmental area (VTA). Selective blockade of cocaineinduced reduction of GABAergic inhibition in the VTA might diminish cocaine-induced aberrant synaptic plasticity and addictive behavior. Here, we investigated the mechanism for cocaine-induced reduction of GABAergic inhibition. We show that a pathophysiologically relevant concentration of cocaine enables a normally ineffective stimulus to induce long-term depression (LTD) of IPSCs (I-LTD) in VTA dopamine neurons of midbrain slices. Activation of D 2 dopamine receptors and group I metabotropic glutamate receptors and subsequent recruitment of endocannabinoid signaling are required for I-LTD induction. We further demonstrate that in vivo pretreatment with antagonists to these receptors blocks cocaine-induced reduction of GABAergic inhibition and that repeated cocaine exposure in vivo occludes the subsequent induction of I-LTD ex vivo. Together, these results suggest that repeated cocaine exposure reduces the strength of GABAergic inhibition in dopamine neurons by inducing I-LTD-like modification in vivo.

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Section: The Implication Of I-ltd In Cocaine-seeking Behaviorsupporting

confidence: 58%

Endocannabinoid Signaling Mediates Cocaine-Induced Inhibitory Synaptic Plasticity in Midbrain Dopamine Neurons

Pan¹,

Hillard²,

Liu³

2008

J. Neurosci.

127

151

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“…Questions regarding the selectivity of MPEP for mGlu5 have been noted previously (Lea and Faden, 2006), and here we report definitive evidence that the in vivo analgesic effects of MPEP in an inflammatory pain condition are not exclusively mediated by antagonism of mGlu5. This finding has specific and immediate implications for the pain field, because MPEP has been the primary antagonist used in assessing the role of mGlu5 in pain for more than a decade (Lea and Faden, 2006). Previous results obtained by a multitude of research groups, including our own, must be considered in light of this new finding.…”

Section: The Selective Mglu5 Antagonist Fenobam Is Analgesic In Mice 841mentioning

confidence: 52%

The Metabotropic Glutamate Receptor Subtype 5 Antagonist Fenobam Is Analgesic and Has Improved in Vivo Selectivity Compared with the Prototypical Antagonist 2-Methyl-6-(phenylethynyl)-pyridine

Montana

Cavallone²,

Stubbert³

et al. 2009

J Pharmacol Exp Ther

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Metabotropic glutamate receptor subtype 5 (mGlu5) has been demonstrated to play a role in the modulation of numerous nociceptive modalities. When administered via peripheral, intrathecal, or systemic routes, mGlu5 antagonists have analgesic properties in a variety of preclinical pain models. Despite a wealth of data supporting the use of mGlu5 antagonists to treat pain, studies have been limited to preclinical animal models due to a lack of mGlu5 antagonists that are approved for use in humans. It has been demonstrated previously that fenobam [N-(3-chlorophenyl)-NЈ-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea], an anxiolytic shown to be safe and effective in human trials, is a selective and potent noncompetitive antagonist of mGlu5 (J Pharmacol Exp Ther 315:711-721, 2005). Here, we report a series of studies aimed at testing whether fenobam, similar to the prototypical mGlu5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP), has analgesic properties in mice. We show that fenobam reduces formalininduced pain behaviors and relieves established inflammationinduced thermal hypersensitivity in mice. Similar results were seen with MPEP. Administration of fenobam resulted in an increase in locomotor activity in the open-field task but did not impair performance on the accelerating Rotarod. Analysis of brain and plasma fenobam levels indicated that fenobam is rapidly concentrated in brain after intraperitoneal administration in mice but is essentially cleared from circulation within 1 h after injection. Fenobam had no analgesic effect in mGlu5 knockout mice, whereas the prototypical antagonist MPEP retained significant analgesic efficacy in mGlu5 knockouts. These results demonstrate that fenobam is analgesic in mice and has an improved in vivo selectivity for mGlu5 over MPEP.

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“…However, we suggest that caution be used in translation to patients with PD and that clinical measures of quality of peak antiparkinsonian benefit, not just on-time and dyskinesia, be included in subsequent patient studies, particularly at phase III. MTEP is a prototypical antagonist of mGlu5 (Cosford al., 2003) that is orally active and of considerably greater selectivity for mGlu5 (Lea and Faden, 2006) than other mGlu5 agents, e.g., MPEP (Breysse et al, 2003;Levandis et al, 2008) and SIB-1830 (Hill et al, 2001), that have been used in some previous studies to assess potential in PD.…”

Section: Discussionmentioning

confidence: 99%

Reduction of l-DOPA-Induced Dyskinesia by the Selective Metabotropic Glutamate Receptor 5 Antagonist 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]pyridine in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Lesioned Macaque Model of Parkinson's Disease

Johnston

Fox²,

McIldowie³

et al. 2010

J Pharmacol Exp Ther

135

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Long-term motor complications of dopamine replacement, such as L-DOPA-induced dyskinesia (LID) and reduced quality of L-DOPA action, remain obstacles in the treatment of Parkinson's disease. Dysfunctional glutamatergic neurotransmitter systems have been observed in both the untreated parkinsonian and dyskinetic states and represent novel targets for treatment. Here, we assess the pharmacokinetic profile and corresponding pharmacodynamic effects on behavior of the orally active, selective metabotropic glutamate receptor type 5 (mGlu5) antagonist, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) (as the hydrochloride salt) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned macaque. Six parkinsonian, MPTP-lesioned cynomolgus monkeys, with established LID, were administered acute challenges with MTEP (4.5-36 mg/kg p.o.) or vehicle, either alone or in combination with L-DOPA (33 Ϯ 1 mg/kg p.o.). Motor activity, parkinsonian disability, and dyskinesia were assessed for a 6-h period. Plasma drug levels were assessed by liquid chromatography-tandem mass spectrometry. MTEP had no antiparkinsonian action as monotherapy. However, administration of L-DOPA in combination with MTEP (36 mg/kg) reduced peak dose LID by 96%. Moreover, although total on-time (duration for which L-DOPA exerted an antiparkinsonian effect) was not significantly reduced, MTEP (36 mg/kg) reduced the duration of on-time with disabling LID by 70% compared with that for L-DOPA alone. These effects were associated with a peak plasma concentration of 20.9 M and an area under the curve from 0 to 24 h of 136.1 h ⅐ M (36 mg/kg). Although total on-time was not reduced, the peak antiparkinsonian benefit of L-DOPA/MTEP (36 mg/kg) was less than that with L-DOPA alone. Selective mGlu5 inhibitors may have significant potential to ameliorate dyskinesia, but care should be taken to ensure that such effects do not come at the expense of the peak antiparkinsonian benefit of L-DOPA.

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Metabotropic Glutamate Receptor Subtype 5 Antagonists MPEP and MTEP

Cited by 147 publications

References 214 publications

Endocannabinoid Signaling Mediates Cocaine-Induced Inhibitory Synaptic Plasticity in Midbrain Dopamine Neurons

Endocannabinoid Signaling Mediates Cocaine-Induced Inhibitory Synaptic Plasticity in Midbrain Dopamine Neurons

The Metabotropic Glutamate Receptor Subtype 5 Antagonist Fenobam Is Analgesic and Has Improved in Vivo Selectivity Compared with the Prototypical Antagonist 2-Methyl-6-(phenylethynyl)-pyridine

Reduction of l-DOPA-Induced Dyskinesia by the Selective Metabotropic Glutamate Receptor 5 Antagonist 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]pyridine in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Lesioned Macaque Model of Parkinson's Disease

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