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.
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 +/- 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 microM and an area under the curve from 0 to 24 h of 136.1 h x microM (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.
Johnston
Tom H
TH
Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Ontario, Canada. tom.johnston@uhnresearch.ca
Fox
Susan H
SH
McIldowie
Matthew J
MJ
Piggott
Matthew J
MJ
Brotchie
Jonathan M
JM
D000818:Animals; D000978:Antiparkinson Agents / Q000633:toxicity*; D001522:Behavior, Animal / Q000187:drug effects; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology / Q000517:prevention & control*; D005260:Female; D007980:Levodopa / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D020267:MPTP Poisoning / Q000517:prevention & control*; D008252:Macaca fascicularis; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control*; D010880:Piperidines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*
C541428:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)piperidine; D000978:Antiparkinson Agents; D010880:Piperidines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; D007980:Levodopa