Effects of dopamine uptake inhibitor MRZ-9547 in animal models of Parkinson's disease.

MRZ-9547 (d-(2-(2-oxo-4(R)-phenylpyrrolidin-1-yl)-acetamide) is a drug acting at the dopamine transporter (DAT). In the present study, effects of MRZ-9547 alone and in combination with L-3,4-dihydroxyphenylalanine (L-DOPA) were investigated in rodent models predictive for efficacy in Parkinson's disease (PD) and L-DOPA-induced dyskinesia (LID). In rats pre-treated with haloperidol (0.2 mg/kg i.p.), MRZ-9547 (25-100 mg/kg i.p.) dose-dependently attenuated decrease in horizontal locomotion, activity in central zone, and rearings starting at 50 mg/kg i.p. In rats depleted of monoamines by α-methyl-p-tyrosine and reserpine treatment, MRZ-9547 attenuated hypolocomotion starting at 100 mg/kg i.p. At the doses 25-100 mg/kg i.p. the drug induced dose-dependent ipsilateral rotations in rats with unilateral 6-hydroxydopamine (6-OHDA)-induced nigrostriatal system lesions. However, MRZ-9547 enhanced contralateral rotation produced by L-DOPA given at an effective (25 mg/kg i.p.), but not at a sub-effective (6.25 mg/kg i.p.) dose. Microdialysis experiments revealed that MRZ-9547 penetrated well to the brain and did not show any pharmacokinetic interaction with L-DOPA. In unilaterally 6-OHDA-lesioned rats having developed abnormal involuntary movements (AIMs, a rodent correlate of LID) after chronic L-DOPA treatment, MRZ-9547 (50 mg/kg i.p.) did not significantly affect the AIMs expression. The results indicate that MRZ-9547 may by itself have antiparkinsonian activity at early stages of the disease, when some dopaminergic terminals are still intact. It may also enhance antiparkinsonian effect of L-DOPA. MRZ-9547 does not seem to influence the expression of LID in 6-OHDA-lesioned rats. The results support the use of MRZ-9547 in PD patients treated with L-DOPA.