The Development of Multi-Target-Directed Ligands (MTDL) to Treat Alzheimer’s Disease
Pp. 86-108 (23)
John W. Wright and Joseph W. Harding
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.
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.
Department of Psychology, Washington State University, Pullman WA, 99164-4820 USA.