Therapeutic and Diagnostic Agents for Parkinson’s Disease

This chapter considers the biology and medical chemistry-based treatment of Parkinson’s disease, the second most common of the major neurodegenerative neuropsychiatric disorders. It surveys basic clinical features, neuropathology, and etiological theories based on genetics, maturational and oxidative-metabolic degenerative processes, and environmental neurotoxins including MPTP. Treatments reviewed include l-dopa as a replacement therapy, direct dopaminergic agonists and their structure-activity relationships, and agents that potentiate dopamine by preventing the metabolism of dopa or dopamine by peripheral aromatic amino acid decarboxylase, catechol-O-methyltransferase, or monoamineoxidase. Drugs acting on nondopaminergic systems considered include anticholinergic, adenosine agonist, glutamate antagonist, and serotonin agonist agents. Agents useful for the diagnosis of Parkinson’s disease and monitoring progression of the disease include radioactive dopa and dopamine transporter labeling agents for use in brain imaging. Finally, future directions of efforts to improve the treatment of Parkinson’s disease are considered, with an emphasis on the continued central importance of medicinal chemistry. Keywords: adenosine antagonists; basal ganglia; COMT inhibitors; decarboxylase inhibitors; dopamine; dopamine agonists; D1 agonists; D2 agonists; ergolines; glutamate antagonists; levodopa; MAO inhibitors; MPTP; neurodegeneration; oxidation; Parkinson’s disease; parkinsonism; pramipexole; radiodiagnostic agents; receptors; ropinirole; serotonin agonists