PT  - JOURNAL ARTICLE
AU  - Emmanuel Le Poul
AU  - Christelle Boléa
AU  - Francoise Girard
AU  - Sonia Poli
AU  - Delphine Charvin
AU  - Brice Campo
AU  - Julien Bortoli
AU  - Abdhelak Bessif
AU  - Bin Luo
AU  - Amy Jo Koser
AU  - Lisa M. Hodge
AU  - Karen M. Smith
AU  - Anthony G. DiLella
AU  - Nigel Liverton
AU  - Fred Hess
AU  - Susan E. Browne
AU  - Ian J. Reynolds
TI  - A Potent and Selective Metabotropic Glutamate Receptor 4 Positive Allosteric Modulator Improves Movement in Rodent Models of Parkinson's Disease
AID  - 10.1124/jpet.112.196063
DP  - 2012 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 167--177
VI  - 343
IP  - 1
4099  - http://jpet.aspetjournals.org/content/343/1/167.short
4100  - http://jpet.aspetjournals.org/content/343/1/167.full
SO  - J Pharmacol Exp Ther2012 Oct 01; 343
AB  - 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 EC50 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 >50-fold the in vitro EC50 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, dose-dependent 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.