Designing prodrugs for the treatment of Parkinson's disease.

INTRODUCTION: Current Parkinson's disease (PD) therapy is essentially symptomatic, and l-Dopa (LD), is the treatment of choice in more advanced stages of the disease. However, motor complications often develop after long-term treatment, and at this point physicians usually prescribe adjuvant therapy with other classes of antiparkinsonian drugs, including dopamine (DA) agonists, catechol-O-methyl transferase (COMT) or monoamine oxidase (MAO)-B inhibitors. In order to improve bioavailability, the prodrug approach appeared to be the most promising, and some antiparkinsonian prodrugs have been prepared in an effort to solve these problems. AREAS COVERED: This review discusses the evidence of progress in PD therapy, mainly focused on prodrug approach for treatment of this neurological disorder. Several derivatives were studied with the aim of enhancing its chemical stability, water or lipid solubility, as well as diminishing the susceptibility to enzymatic degradation. Chemical structures mainly related to LD, DA and dopaminergic agonists are also reviewed in this paper. EXPERT OPINION: In order to strengthen the pharmacological activity of antiparkinsonian drugs, enhancing their penetration of the blood-brain barrier (BBB), different approaches are possible. Among these, the prodrug approach appeared to be the most promising, and many prodrugs have been prepared in an effort to optimize physicochemical characteristics. In addition, novel therapeutic strategies based on formulations linking dopaminergic drugs with neuroprotective agents, increasing LD striatal levels and offering sustained release of the drug without any fluctuation of brain concentration, offer promising avenues for development of other effective new treatments for PD.