Deuterium-L-DOPA : a novel means to improve treatment of Parkinson's disease

Abstract

L-DOPA, the precursor of dopamine, is administered to restore dopamine deficiency in Parkinson´s disease (PD) patients. L-DOPA initially provides a sustained symptomatic relief with superior efficacy as compared to other treatments, while long term treatment is complicated by the gradual emergence of troublesome motor complications i.e. fluctuations in therapeutic effect and L-DOPA-induced dyskinesia. The risk for motor complications is associated with disease duration and total L-DOPA load. While the underlying mechanisms remain to be fully elucidated, the inability of the remaining dopaminergic neurons to buffer exogenously applied L-DOPA and pulsatile stimulation of dopamine receptors resulting from the short half-life of the drug seem critical. An improved treatment strategy with similar efficacy as L-DOPA and reduced side effects is therefore highly warranted.

Deuterium-L-DOPA was expected to yield dopamine more resistant to enzymatic degradation, as deuterium, heavy hydrogen, forms a stronger bond with carbon. Four isoforms of deuterium-L-DOPA, carrying different combinations of α and β carbon substitutions, were screened for isotope effects on striatal dopamine metabolism by means of in vivo microdialysis in intact rats. The triple substituted isoform, α,β,β-D3-L-DOPA (D3-L-DOPA), dramatically increased the duration of dopamine output and reduced noradrenaline output as compared to L-DOPA. These effects most likely reflect reduced activity of the dopamine metabolizing enzymes MAO and DβH towards the deuterium substituted α- and β- carbons, respectively. Deuterium substitutions thus increase the half-life of dopamine formed from L-DOPA, which may reduce pulsatile stimulation of dopamine receptors as well as the total L-DOPA load in PD patients. The improved central kinetics of D3-L-DOPA may thereby significantly reduce the risk for L-DOPA induced motor complications. Reduced output of noradrenaline from D3-L-DOPA may additionally contribute to reduce the side effect profile, as noradrenaline released from L-DOPA may be involved in the expression of dyskinesias.

The neurochemical and behavioral effects of D3-L-DOPA were subsequently evaluated in two, well-established animal models of PD, the reserpine and the 6-OHDA-lesion model. D3-L-DOPA produced an increased dopamine output as compared to L-DOPA in the 6-OHDA-lesioned striatum; an effect which closely resembled that of L-DOPA in combination the MAO-B inhibitor selegiline; used in clinical practice to potentiate the symptomatic effect of L-DOPA and reduce motor fluctuations. Moreover, selegiline pre-treatment did not potentiate the effect of D3-L-DOPA. The enhanced output of dopamine from D3-L-DOPA and selegiline/L-DOPA may thus be attributed to decreased metabolism of dopamine at MAO-B containing sites.

An acute challenge with D3-L-DOPA was shown to produce an increased motor activation as compared to L-DOPA in both models of PD, indicating an increased behavioral potency. In addition, the behavioral effect produced by D3-L-DOPA was found to be of similar magnitude as the combination of selegiline/L-DOPA. Our data hence provide experimental support for the potential clinical advantage of D3-L-DOPA and suggest that monotherapy with D3-L-DOPA may provide equal benefit as the combination of selegiline/L-DOPA.The effects of D3-L-DOPA and L-DOPA were also compared in a chronic treatment design. Significantly, a lower dose of D3-L-DOPA, 60% of the equivalent L-DOPA dose, produced similar anti-parkinsonian benefit while the expression of dyskinesias was markedly reduced. The equivalent dose of D3-L-DOPA, as compared to L-DOPA, produced a more pronounced anti-parkinsonian effect and similar expression of dyskinesia. Taken together, these findings indicate that deuterium substitutions offer the advantage of a wider therapeutic window.

In conclusion, the increased half-life of dopamine formed from D3-L-DOPA may serve to protect dopamine receptors from pulsatile stimulation and the increased behavioral potency of D3-L-DOPA may allow for adequate control of parkinsonian symptoms at an overall lower dosage. Altogether, a reduced L-DOPA load and more sustained stimulation of dopamine receptors may substantially improve PD treatment by reducing the risk for motor fluctuations and dyskinesias. Our preclinical data thus provide support for the utility of deuterium-substitutions in the L-DOPA molecule as a means to improve the therapeutic effect and reduce the side effects of L-DOPA therapy.