Design, synthesis and evaluation of novel levodopa pro-drugs for the treatment of Parkinson's disease
Parkinson's disease is a slowly progressive neurodegenerative disorder of unknown cause that selectively affects the dopaminergic, extrapyramidal nigrostriatal pathway. Parkinson's disease is a mid- or late life disease, presenting most often at ages 55-65, affecting 1-2% of the population over the age of 65. Current therapy is essentially symptomatic, and L-dopa, the direct precursor of dopamine, is the treatment of choice in more advanced stages of the disease. The oral bioavailability of L-dopa is estimated to be about 10% and less than 1% of the administered oral dose reaches the brain unchanged. In an attempt to overcome the problems with peripheral L-dopa metabolism, delivery difficulties and insufficient conversion of L-dopa to dopamine in the brain tissue, L-dopa prodrugs are proposed in this study. An L-dopa-lazabemide prodrug was thus proposed to overcome the problems associated with L-dopa absorption and delivery to the brain. Lazabemide, a monoamine oxidase (MAO) B inhibitor, slows depletion of dopamine stores and elevates dopamine levels produced by exogenously administered L-dopa. L-Dopa was linked at the carboxylate with the primary aminyl functional group of lazabemide via an amide, a strategy which is anticipated to protect L-dopa against peripheral decarboxylation and possibly also enhance the membrane permeability of the prodrug. Selected physicochemical and biochemical properties of the prodrug were determined. Although oral and i.p. treatment of mice with the prodrug did not result in an enhancement of striatal dopamine levels, DOPAC (Dihydroxyphenyl acetic acid) levels were significantly depressed compared to saline, L-dopa and carbidopa/L-dopa treatment. Secondly, in another attempt to overcome L-dopa's limited bioavailability and brain penetration, the present study synthesises four carrier-linked prodrugs of L-dopa in which 4-pyridylmethylamine, 2-(4-pyridyl)ethylamine, 2-(2-pyridyl)ethylamine and 3-phenyl-1-propylamine are linked to the carboxylate of L-dopa. Key physicochemical and biochemical parameters of the prodrugs were evaluated in an attempt to assess the potential of these prodrugs as vehicles to enhance the absorption and central delivery of L-dopa. Although the development of lazabemide has been discontinued, this compound is still used as reference MAO-B inhibitor in the in vitro screening of experimental MAO inhibitors. The third section of the present study aimed to characterise the in vitro MAO inhibition properties of lazabemide with respect to potency, isoform selectivity and reversibility. The results show that lazabemide is a selective inhibitor of human MAO-B with an IC50 value of 0.091 μM. For human MAO-A, lazabemide exhibits an IC50 of >100 μM. Interestingly, dialysis restores MAO-B activity only to a very small extent following inhibition by lazabemide, which shows that, in vitro inhibition persists and lazabemide may be viewed as an irreversible MAO-B inhibitor. Irreversible MAO inhibitors of the well-known propargylamine class include drugs that have been used clinically such as pargyline, selegiline and rasagiline, specifically for the treatment of depression and as adjuvants to L-dopa in Parkinson's disease. Due to their importance as MAO inhibitors, the fourth part of the present study synthesises a small series of novel propargylamine compounds that incorporate the pyridyl moiety. Pyridyl-derived propargylamines have not yet been investigated as potential MAO inhibitors. This study finds that the pyridyl-derived propargylamines do not inhibit either of the human MAO isoforms.
- Health Sciences