Drug design in Parkinson's disease : from caffeine to promising leads / Jacques Petzer

Abstract

The treatment of Parkinson’s disease is insufficient and novel, more effective drugs are needed. An established molecular target for the design of drugs for the treatment of Parkinson’s disease is the enzyme, monoamine oxidase (MAO), particularly the MAO-B isoform. Inhibitors of MAO-B are well-known drugs for the treatment of Parkinson’s disease since these compounds block the catabolism of dopamine by the MAO-B enzyme. This prevents the depletion of dopamine reserves and enhances the duration of the physiological action of dopamine. Inhibitors of MAO-B may also act as neuroprotective agents, further cementing a role for this class of drugs in Parkinson’s disease. Caffeine, a small molecule of natural origin, is an appropriate lead compound for the design of MAO-B inhibitors. This address discusses recent studies that aim to discover new caffeine-derived MAO-B inhibitors. In this respect, substitution with a relatively wide variety of moieties at C8 of caffeine yields highly potent MAO-B inhibitors. Although less frequently observed, substitution at C8 also yields highly potent MAO-A inhibitors. Since MAO-A inhibitors are used in the treatment of depression, dual-acting compounds that block the activities of both MAO-A and MAO-B may be of importance in the therapy of Parkinson’s disease that is associated with depression.