Pharmacotherapy Evolution in Alzheimer's Disease: Current Framework and Relevant Directions

Abstract

Alzheimer's disease (AD), once considered a rare disease, is now the most common form of dementia in the elderly population. Current drugs (cholinesterase inhibitors and glutamate antagonists) are safe but of limited benefit to most patients, offering symptomatic relief without successful cure of the disease. Since the last several decades, there has been a great need for the development of a treatment that might cure the underlying causes of AD and thereby slow its progression in vulnerable individuals. That is why phase I, II, and III studies that act on several fronts, such as cognitive improvement, symptom reduction, and enhancing the basic biology of AD, are imperative to stop the disease. This review discusses current treatment strategies, summarizing the clinical features and pharmacological properties, along with molecular docking analyses of the existing medications.

Keywords: Alzheimer’s disease; cholinesterase inhibitors; cognitive improvement; glutamate antagonists; symptom reduction.

Figure 1

The main drugs and their chemical structure approved in the treatment of Alzheimer’s disease.

Figure 2

2D and 3D representation of the ligand–protein complex; (a) donepezil–AChE (A chain) complex; (b) donepezil–AChE (B chain) complex; (c) 3D structure of donepezil–AChE (chain A) complex; (d) 3D of donepezil–AChE (chain B) complex. Legend: GLY—glycine; TYR—tyrosine; TRP—tryptophan; PHE—phenylalanine; LEU—leucine. The letters A and B represent the chain; the number represents the numbering of the amino acid.

Figure 3

2D and 3D diagrams representing the links between ligand and protein; (a) rivastigmine–AChE (chain A) complex; (b) rivastigmine–AChE (chain B) complex; (c) 3D structure of the donepezil—AChE (chain A) complex A; (d) 3D structure of the donepezil–AChE (chain B) complex. Legend: TYR—tyrosine; TRP—tryptophan; PHE—phenylalanine; LEU—leucine; SER—serine; ARG—arginine; GLU—glutamic acid. The letters A and B represent the chains; the number represents the numbering of the amino acid.

Figure 4

2D and 3D representation of the ligand–protein complex; (a) galantamine–AChE (chain A) complex; (b) galantamine–AChE (chain B) complex; (c) 3D structure of the galantamine–AChE (chain A) complex; (d) 3D structure of the galantamine–AChE (chain B) complex. Legend: TYR—tyrosine; TRP—tryptophan; PHE—phenylalanine; LEU—leucine. The letters A and B represent the chain, and the number represents the numbering of the amino acid.

Figure 5

2D and 3D diagrams representing the link between memantine and NMDA; (a) 2D representation of the memantine- NMDA complex; (b) 3D representation of the Memantine—NMDA complex. Legend: ILE—isoleucine; MET—methionine; the letters C and D represent the chain, and the number represents the numbering of the amino acid.

Figure 6

Cleavage of APP. In the normal conditions, APP is cleaved by α-secretase. In abnormal conditions, APP will be cleaved by β-secretase, resulting in the accumulation and aggregations of small peptides called β-amyloid (Aβ), with the formation of amyloid plaques.

Figure 7

Main findings and directions of this research.