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 >50-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, 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.