Antiparkinson Prodrugs

Abstract

Parkinson’s disease (PD) is a progressive, neurodegenerative disorder which involves the loss of dopaminergic neurons of the substantia nigra pars compacta. Current therapy is essentially symptomatic, and L-Dopa (LD), the direct precursor of dopamine (DA), is the treatment of choice in more advanced stages of the disease. Substitution therapy with LD is, however, associated with a number of acute problems. The peripheral conversion of LD by amino acid decarboxylase (AADC) to DA is responsible for the typical gastrointestinal (nausea, emesis) and cardiovascular (arrhythmia, hypotension) side effects. To minimize the conversion to DA outside the central nervous system (CNS) LD is usually given in combination with peripheral inhibitors of AADC (carbidopa and benserazide). In spite of that, other central nervous side effects such as dyskinesia, on-off phenomenon and end-of-dose deterioration still remain. The main factors responsible for the poor bioavailability and the wide range of inter- and intra-patient variations of plasma levels are the drug’s physical-chemical properties: low water and lipid solubility, resulting in unfavourable partition, and the high susceptibility to chemical and enzymatic degradation. In order to improve the bioavailability, the prodrug approach appeared to be the most promising and some LD prodrugs have been prepared in an effort to solve these problems. We report here a review of progress in antiparkinson prodrugs, focusing on chemical structures mainly related to LD, DA and dopaminergic agonists.

Novel approaches on prodrug based drug design

“…The main factors responsible for the poor bioavailability and the wide range of inter-and intrapatient variations of plasma levels are the drug's physical-chemical properties like low water and lipid solubility, resulting in unfavorable partition, and the high susceptibility to chemical and enzymatic degradation. In order to improve the bioavailability, the prodrug approach appeared to be the most promising and some LD prodrugs have been prepared in an effort to solve these problems [58]. Furthermore, Bodor and Farag [59] proposed the application of a chemical delivery system based on a pyridinium/dihydropyridine redox carrier for brain-specific delivery of DA.…”

Levodopa: Past, Present, and Future

“…In contrast, for XP21279, the mean T max was 4.3 h and the ratio of C max to C 12 was 4.2, suggesting relatively continuous levodopa levels. Additional levodopa prodrugs are in development [76], but as yet, no clinical results have been reported.…”

Mesencephalic Astrocyte-Derived Neurotrophic Factor Is Neurorestorative in Rat Model of Parkinson's Disease

“…The movement disorder is mainly a consequence of degeneration of dopamine (DA) neurons projecting from the substantia nigra (SN) to the caudate-putamen. Current therapies of PD provide relief of motor symptoms but do not prevent disease progression (Di Stefano et al, 2008). Thus, there is a need for therapies that can slow down neurodegeneration and restore the function of neural circuits controlling movements.…”