Metabotropic glutamate receptor 4 (mGlu4) positive allosteric modulators lack efficacy in rat and marmoset models of L-DOPA-induced dyskinesia

TY - JOUR

T1 - Metabotropic glutamate receptor 4 (mGlu4) positive allosteric modulators lack efficacy in rat and marmoset models of L-DOPA-induced dyskinesia

AU - Duty, Susan

AU - Finlay, Clare

AU - Jackson, Michael

AU - Salvage, Sarah

AU - Fisher, Ria

AU - Bundgaard, Christoffer

PY - 2024/3/5

Y1 - 2024/3/5

N2 - Background: Increased activity across corticostriatal glutamatergic synapses may contribute to L-DOPA-induced dyskinesia in Parkinson’s disease. Given the weak efficacy and side-effect profile of amantadine, alternative strategies to reduce glutamate transmission are being investigated. Metabotropic glutamate receptor 4 (mGlu4) is a promising target since its activation would reduce glutamate release. Objectives: We hypothesised that two mGlu4 positive allosteric modulators, Lu AF21934 ((1S,2R)-2-[(aminooxy) methyl]-N-(3,4-dichlorophenyl)cyclohexane-1-carboxamide) and ADX88178 (5-Methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine), would provide relief in rat and primate models of L-DOPA-induced dyskinesia. Methods: The ability of Lu AF21934 or ADX88178 to reverse pre-established dyskinesia was examined in L-DOPA-primed 6-hydroxydopamine-lesioned rats expressing abnormal involuntary movements (AIMs) or in 1-methyl-4-phenyl,1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets expressing L-DOPA-induced dyskinesia. Additionally, the ability of Lu AF21934 to prevent the development of de novo L-DOPA-induced AIMs was explored in the 6-hydroxydopamine-lesioned rats. Results: Neither Lu AF21934 (10 or 30 mg/kg p.o.) nor ADX88178 (10 or 30 mg/kg p.o.) reduced pre-established AIMs in 6-hydroxydopamine-lesioned rats. Similarly, in L-DOPA-primed common marmosets, no reduction in established dyskinesia was observed with Lu AF21934 (3 or 10 mg/kg p.o.). Conversely, amantadine significantly reduced (>40%) the expression of dyskinesia in both models. Lu AF21934 also failed to suppress the development of AIMs in 6-hydroxydopamine-lesioned rats. Conclusions: This study found no benefit of mGlu4 positive allosteric modulators in tackling L-DOPA-induced dyskinesia. These findings are concordant with the recent failure of foliglurax in phase II clinical trials supporting the predictive validity of these pre-clinical dyskinesia models, while raising further doubt on the anti-dyskinetic potential of mGlu4 positive allosteric modulators.

AB - Background: Increased activity across corticostriatal glutamatergic synapses may contribute to L-DOPA-induced dyskinesia in Parkinson’s disease. Given the weak efficacy and side-effect profile of amantadine, alternative strategies to reduce glutamate transmission are being investigated. Metabotropic glutamate receptor 4 (mGlu4) is a promising target since its activation would reduce glutamate release. Objectives: We hypothesised that two mGlu4 positive allosteric modulators, Lu AF21934 ((1S,2R)-2-[(aminooxy) methyl]-N-(3,4-dichlorophenyl)cyclohexane-1-carboxamide) and ADX88178 (5-Methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine), would provide relief in rat and primate models of L-DOPA-induced dyskinesia. Methods: The ability of Lu AF21934 or ADX88178 to reverse pre-established dyskinesia was examined in L-DOPA-primed 6-hydroxydopamine-lesioned rats expressing abnormal involuntary movements (AIMs) or in 1-methyl-4-phenyl,1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets expressing L-DOPA-induced dyskinesia. Additionally, the ability of Lu AF21934 to prevent the development of de novo L-DOPA-induced AIMs was explored in the 6-hydroxydopamine-lesioned rats. Results: Neither Lu AF21934 (10 or 30 mg/kg p.o.) nor ADX88178 (10 or 30 mg/kg p.o.) reduced pre-established AIMs in 6-hydroxydopamine-lesioned rats. Similarly, in L-DOPA-primed common marmosets, no reduction in established dyskinesia was observed with Lu AF21934 (3 or 10 mg/kg p.o.). Conversely, amantadine significantly reduced (>40%) the expression of dyskinesia in both models. Lu AF21934 also failed to suppress the development of AIMs in 6-hydroxydopamine-lesioned rats. Conclusions: This study found no benefit of mGlu4 positive allosteric modulators in tackling L-DOPA-induced dyskinesia. These findings are concordant with the recent failure of foliglurax in phase II clinical trials supporting the predictive validity of these pre-clinical dyskinesia models, while raising further doubt on the anti-dyskinetic potential of mGlu4 positive allosteric modulators.

U2 - 10.3233/JPD-230296

DO - 10.3233/JPD-230296

M3 - Article

SN - 1877-7171

JO - Journal of Parkinson's Disease

JF - Journal of Parkinson's Disease

ER -