The Development of Multi-Target-Directed Ligands (MTDL) to Treat Alzheimer’s Disease

The loss of neurons and synapses resulting in neurotransmitter dysfunction, along with β-amyloid peptide (Aβ) aggregation and neurofribrillary tangles, have served as the hallmarks of Alzheimer’s disease (AD). Alterations associated with neurochemical disturbances of several neurotransmitter systems appear to be the major underling cause of the cognitive and neuropsychiatric symptoms accompanying this disease. Treatments designed to target cholinergic deficiencies have provided only minimal benefit to the large majority of AD patients. As populations live longer there is a persistent and growing need for the development of new and much more efficacious treatment strategies designed to prevent progressive synaptic and neuron losses and encourage neurogenesis and synaptogenesis. There is also the emerging realization that neurodegenerative diseases such as AD, Parkinson’s disease, and Amyotrophic Lateral Sclerosis are the result of multiple insults, not one or two, and must be countered with multi-target lead compounds. The development of these new drugs requires a reevaluation of high throughput screens against protein targets in favor of the development of multi-target-directed ligands (MTDL) consisting of a single or hybrid compound capable of influencing several targets and/or systems. The present chapter focuses on this MTDL approach in the development of drugs to treat AD, but recognizes that this drug design strategy is applicable to other clinically significant diseases. This new approach represents a transition away from the “one molecule one target” high throughput screening assays, toward the rational design of drugs. As such it ushers in a new approach to drug development.

Keywords: Aβ aggregate, Acetylcholinesterase inhibitor drugs, Alzheimer’s disease, Angiotensin receptor blocking drugs, AT4 receptor subtype, Brain reninangiotensin system, β-secretase, Cerebral blood flow, c-Met receptor, Dementia, Drug development strategies, MAO inhibitor drugs, Multi-target-directed drugs, Neurogenesis, NMDA receptor antagonist drugs, Oxidative stress, Parkinson’s disease-induced dementia, Synaptogenesis.