ArticlePublisher preview availableLiterature Review

Multi-Target Drug Candidates for Multifactorial Alzheimer’s Disease: AChE and NMDAR as Molecular Targets

January 2021
Molecular Neurobiology

DOI:10.1007/s12035-020-02116-9

Authors:

Wenzhou Medical University

Alzheimer’s disease (AD) is one of the most common forms of dementia among elder people, which is a progressive neurodegenerative disease that results from a chronic loss of cognitive activities. It has been observed that AD is multifactorial, hence diverse pharmacological targets that could be followed for the treatment of AD. The Food and Drug Administration has approved two types of medications for AD treatment such as cholinesterase inhibitors (ChEIs) and N-methyl-D-aspartic acid receptor (NMDAR) antagonists. Rivastigmine, donepezil, and galantamine are the ChEIs that have been approved to treat AD. On the other hand, memantine is the only non-competitive NMDAR antagonist approved in AD treatment. As compared with placebo, it has been revealed through clinical studies that many single-target therapies are unsuccessful to treat multifactorial Alzheimer’s symptoms or disease progression. Therefore, due to the complex nature of AD pathophysiology, diverse pharmacological targets can be hunted. In this article, based on the entwined link of acetylcholinesterase (AChE) and NMDAR, we represent several multifunctional compounds in the rational design of new potential AD medications. This review focus on the significance of privileged scaffolds in the generation of the multi-target lead compound for treating AD, investigating the idea and challenges of multi-target drug design. Furthermore, the most auspicious elementary units for designing as well as synthesizing hybrid drugs are demonstrated as pharmacological probes in the rational design of new potential AD therapeutics.

The chemical structure of the heterotrimer of donepezil, chromone and melatonin

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The chemical structure of the heterodimer of memantine and 6-chlorotacrine

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Multi-Target Drug Candidates for Multifactorial Alzheimer’s Disease:

AChE and NMDAR as Molecular Targets

Md. Sahab Uddin

1,2

&Abdullah Al Mamun

1,2

&Md. Tanvir Kabir

&Ghulam Md Ashraf

4,5

&May N. Bin-Jumah

Mohamed M. Abdel-Daim

7,8

Received: 29 July 2020 /Accepted: 2 September 2020

#Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract

Alzheimer’s disease (AD) is one of the most common forms of dementia among elder people, which is a progressive neurode-

generative disease that results from a chronic loss of cognitive activities. It has been observed that AD is multifactorial, hence

diverse pharmacological targets thatcould be followed for the treatment of AD. The Food and Drug Administration has approved

two types of medications for AD treatment such as cholinesterase inhibitors (ChEIs) and N-methyl-D-aspartic acid receptor

(NMDAR) antagonists. Rivastigmine, donepezil, and galantamine are the ChEIs that have been approved to treat AD. On the

other hand, memantine is the only non-competitive NMDAR antagonist approved in AD treatment. As compared with placebo, it

has been revealed through clinical studies that many single-target therapies are unsuccessful to treat multifactorial Alzheimer’s

symptoms or disease progression. Therefore, due tothe complex nature of AD pathophysiology,diverse pharmacological targets

can be hunted. In this article, based on the entwined link of acetylcholinesterase (AChE) and NMDAR, we represent several

multifunctional compounds in the rational design of new potential AD medications. This review focus on the significance of

privileged scaffolds in the generation of the multi-target lead compound for treating AD, investigating the idea and challenges of

multi-target drug design. Furthermore, the most auspicious elementary units for designing as well as synthesizing hybrid drugs

are demonstrated as pharmacological probes in the rational design of new potential AD therapeutics.

Keywords Alzheimer’s disease .Multi-target drugs .Multi-target-directed ligands .AChE .NMDAR

Introduction

Alzheimer’s disease (AD) is the utmost recurrent cause of

dementia that causes a severe loss of cognitive functions [1,

2]. This multifactorial neurodegenerative disorder is charac-

terized by nerve cell death, intracellular neurofibrillary tangles

(NFTs), and extracellular amyloid plaques [3–6]. It is well

known that these plaques are made of amyloid beta (Aβ),

which is a cleavage product of amyloid precursor protein

(APP) [7]. Furthermore, Aβmonomers gradually aggregate

into oligomers, fibrils, and insoluble amyloid plaques [8,9].

NFTs are aggregates of the hyperphosphorylated tau protein.

The stabilization of microtubules is promoted by tau under

normal conditions [10]. However, hyperphosphorylated tau

accumulates as paired helical filaments that subsequently

leads to NFTs [11,12]. Neuronal and synaptic functions are

dysregulated due to Aβaccumulation, which further makes

the intracellular conditions for NFTs formation eventu-

ally leading to neuronal loss that lead to the disturbance

in the functions of neurotransmitters [13–15].

In the basal forebrain, cholinergic neuron loss is assumed

to mediate cholinergic impairment, which eventually leads to

short-term memory loss in AD [16,17]. Thus, a deterioration

in the cholinergic markers and acetylcholine (ACh) are well-

reported in the brains of individuals with AD [18–20]. It was

observed that neuronal cell survival was compromised due to

*Md. Sahab Uddin

msu-neuropharma@hotmail.com; msu_neuropharma@hotmail.com

Department of Pharmacy, Southeast University, Dhaka, Bangladesh

Pharmakon Neuroscience Research Network, Dhaka, Bangladesh

Department of Pharmacy, Brac University, Dhaka, Bangladesh

King Fahd Medical Research Center, King Abdulaziz University,

Jeddah, Saudi Arabia

Department of Medical Laboratory Technology, Faculty of Applied

Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia

Department of Biology, College of Science, Princess Nourah bint

Abdulrahman University, Riyadh 11474, Saudi Arabia

Department of Zoology, College of Science, King Saud University,

P.O. Box 2455, Riyadh 11451, Saudi Arabia

Pharmacology Department, Faculty of Veterinary Medicine, Suez

Canal University, Ismailia 41522, Egypt

https://doi.org/10.1007/s12035-020-02116-9

/ Published online: 15 September 2020

Molecular Neurobiology (2021) 58:281–303

Content courtesy of Springer Nature, terms of use apply. Rights reserved.

A Novel Design Of A Portable Birdcage Via Meander Line Antenna (MLA) To Lower Beta Amyloid (Aβ) In Alzheimer’s Disease

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In Phase II-B will validate the device in a physical phantom. Phase III will require the FDA approval and application in clinical trials. Results: The research parameters were translated into a designed product that fits comfortably in human head and fed from an external RF source that generates an RF power deposition with a SAR of 0.4-0.9 W/kg to a realistic numerical brain. The engineering design is flexible by varying the leg capacitors of the Meander Line Antenna (MLA) devices. Thermal outcomes of the results guarantee less than 0.5 C temperature increase within one-hour time of exposure, which can be used in clinical trials for AD patients. Design parameters include dimension of the coil, the MLA structure, conducting material, and capacitance values with the produced EM fields. The flexible design was achieved by varying the additive capacitance between conductors, and via a hybrid approach integrating a birdcage with sixteen MLA. 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