Altered behavioural and neurochemical profile of L-DOPA following deuterium substitutions in the molecule.
In Parkinson's disease patients, a prolonged half-life of dopamine formed from L-DOPA may reduce the risk of developing L-DOPA-induced side-effects. Deuterium substitutions in the L-DOPA molecule are expected to yield dopamine with an altered half-life because C-D bonds are more stable than C-H bonds. Therefore we tested, in the rat, the neurochemical and behavioral effects of different types of L-DOPA with deuterium substitutions at the alpha-carbon and/or the beta-carbon. By means of microdialysis, we found that L-DOPA with 3 deuterium substitutions (D3-L-DOPA) enhanced dopamine output in the striatum more effectively than L-DOPA and all the other deuterium variants. Moreover, D3-L-DOPA produced a more pronounced stimulation of locomotor activity in reserpinized rats compared to conventional L-DOPA. In contrast beta,beta-D2-L-DOPA was less effective than L-DOPA in raising striatal dopamine levels and was ineffective at restoring locomotor activity in reserpinized rats. These results demonstrate that the introduction of deuterium at different positions in the L-DOPA molecule dramatically changes its behavioral and neurochemical profile and suggest that L-DOPA treatment of Parkinson's disease may be improved in this way.
Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, 171 77 Stockholm, USA.
Torun
T
Malmlöf
Torgny H
TH
Svensson
Björn
B
Schilström
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects*; D002230:Carbidopa / Q000494:pharmacology; D003903:Deuterium / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D007980:Levodopa / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D015259:Dopamine Agents; D015102:3,4-Dihydroxyphenylacetic Acid; D007980:Levodopa; D003903:Deuterium; D002230:Carbidopa; D004298:Dopamine