A Potent and Selective Metabotropic Glutamate Receptor 4 Positive Allosteric Modulator Improves Movement in Rodent Models of Parkinson's Disease

Abstract

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGluR4) have been proposed as a novel therapeutic approach for the treatment of Parkinson's disease. However, evaluation of this proposal has been limited by the availability of appropriate pharmacological tools to interrogate the target. In this study, we describe the properties of a novel mGluR4 PAM. 5-Methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine (ADX88178) enhances glutamate-mediated activation of human and rat mGluR4 with EC 50 values of 4 and 9 nM, respectively. The compound is highly selective for mGluR4 with minimal activities at other mGluRs. Oral administration of ADX88178 in rats is associated with high bioavailability and results in cerebrospinal fluid exposure of Ͼ50-fold the in vitro EC 50 value. ADX88178 reverses haloperidol-induced catalepsy in rats at 3 and 10 mg/kg. It is noteworthy that this compound alone has no impact on forelimb akinesia resulting from a bilateral 6-hydroxydopamine lesion in rats. However, coadministration of a low dose of L-DOPA (6 mg/kg) enabled a robust, dosedependent reversal of the forelimb akinesia deficit. ADX88178 also increased the effects of quinpirole in lesioned rats and enhanced the effects of L-DOPA in MitoPark mice. It is noteworthy that the enhancement of the actions of L-DOPA was not associated with an exacerbation of L-DOPA-induced dyskinesias in rats. ADX88178 is a novel, potent, and selective mGluR4 PAM that is a valuable tool for exploring the therapeutic potential of mGluR4 modulation. The use of this novel tool molecule supports the proposal that activation of mGluR4 may be therapeutically useful in Parkinson's disease.

Characterization of the Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 ADX88178 in Rodent Models of Neuropsychiatric Disorders

“…Specifically, in all assays in rats and mice, with the exception of FST, the MED of ADX88178 was associated with mean plasma concentrations in the range of 220-625 ng/ml. These plasma concentrations are well aligned with the 241 ng/ml plasma concentration of ADX88178 associated with the MED of ADX88178 in the haloperidolinduced catalepsy test (3 mg/kg; Le Poul et al, 2012). However, in the MB test, the ED 50 and CSF EC 50 values (4.5 mg/kg and 121 nM, respectively) were higher than corresponding measures in the haloperidol-induced catalepsy test (1.1 mg/kg and 23 nM, respectively).…”

“…Previously, using intracellular calcium mobilization assays in human embryonic kidney 293 cells expressing the human and rat mGlu 4 receptor, ADX88178 potentiated the response to glutamate with EC 50 values of 3.5 and 9.1 nM, respectively (Le Poul et al, 2012).…”

“…When assessed in vitro, ADX88178 enhances glutamatemediated activation of the human and rat mGlu 4 receptor with EC 50 values of 4 and 9 nM, respectively (Le Poul et al, 2012). When evaluated in vivo, ADX88178 dose-dependently reduced haloperidol-induced catalepsy and potentiated effects of L-DOPA in the forelimb akinesia assay, when performed in rats with bilateral 6-hydroxydopamine lesions of the striatum (Le Poul et al, 2012). In the present report, the anxiolytic-and anti-obsessive compulsive disorder (OCD)-like efficacy of ADX88178 was assessed in the mouse MB test and the EPM test in mice and rats.…”

Overlapping binding sites drive allosteric agonism and positive cooperativity in type 4 metabotropic glutamate receptors

“…To date, no such comparison has been made between these 2 types of mGlu 4 PAMs. All types of mGlu 4 activators, agonists, ago-PAMs, and PAMs exhibiting high degree of cooperativity have been shown to be active in vivo (8,11,33,43,44,(48)(49)(50)(51). It can be speculated that pure mGlu 4 PAMs may be devoid of side effects but, to date, no clear adverse effect has been observed (8,50,51).…”

Expression of metabotropic glutamate receptor 4 in osteosarcoma

“…Moreover, enhanced mGluR4 expression following PHCCC treatment was beneficial in medulloblastomas, and was found to be negatively correlated with neural tube cell tumor progression. Thus, the stimulation of mGlu4 expression may be used to treat Parkinson's disease in addition to medulloblastomas (12). Additionally, these findings suggest that mGluR4 may be considered as a phenotypic marker of medulloblastomas of lower malignant potential, such as the nodular desmoplastic histotype, or may negatively regulate tumor growth.…”