CNS Targets for multi-functional drugs in the treatment of Alzheimer’s and Parkinson’s diseases

Summary.

Patients with mild forms of dementia and age-related memory impairment have just begun to benefit from pharmacotherapy developed over the last several years. However, current approaches do not significantly modify the course of neurodegeneration or of the aging process, and they offer limited and transient benefit to many patients. The goal of this review is to summarize new potential approaches in which molecules have been developed expressly to target multiple brain systems for the treatment of memory and cognition impairment. Some of these approaches include the development of single molecular entities that combine activity as cholinesterase inhibitors, muscarinic cholinergic M2 receptor antagonists, nicotinic acetylcholine receptor agonists, α₂-adrenergic agonists, or monoamine oxidase inhibitors. Many of the bi-functional compounds discussed have improved efficacy as cognitive enhancing agents and/or they offer potential for neuroprotection and disease modification. It is likely that syndromes such as Alzheimer’s disease will require multiple drug therapy to address the varied pathological aspects of the disease. Even if the strategy of combining drugs with different therapeutic targets is workable, the development of multi-functional compounds will obviate the challenge of administering multiple single drug entities with potentially different degrees of bioavailability, pharmacokinetics, and metabolism. Also, the simplification of the therapeutic regimen for individuals with AD who have difficulty with compliance is important.