Biological activities and Chemical moieties as Scaffold for the design of Pharmacological lead compounds for Alzheimer's disease
Divya Sharma1, Akanksha Singh1, Himanshu Gupta1, Diksya Sharma1, Pooja Singh1,
Arjun Singh2*
1Department of Pharmacognosy, School of Pharmaceutical Sciences,
Bhagwant University, Sikar Road, Ajmer, Rajasthan 305004, India.
2Department of Medicine, Sidney Kimmel Medical College,
Thomas Jefferson University, Philadelphia, PA 19107, United States.
*Corresponding Author E-mail: arjunphar@gmail.com
ABSTRACT:
Alzheimer's disease (AD) is a major problem in today's societies. More than five million Americans are living with Alzheimer's disease in the United States, with the majority being 65 and older. According to the Alzheimer's Association Report, the number of persons affected by Alzheimer's disease in the United States would rise to fourteen million by 2060.Alzheimer's disease (AD) is a neurodegenerative disorder characterized by impaired synaptic transmission and brain atrophy, as well as the formation of amyloid plaques and neurofibrillary tangles. The condition is usually associated with cognitive, functional, and behavioural changes. Several pathophysiological paths for Alzheimer's disease have been hypothesized, some of which interact and influence one another. Current Alzheimer's disease treatment focuses on using therapeutic drugs to reduce symptoms in Alzheimer's patients. Because of the disease's complex nature, standard single-target therapeutic techniques frequently fail to have the desired impact. As a result, multi-target methods have been developed, with the goal of simultaneously targeting various targets involved in the development of AD. This paper provides an outline of the pathophysiology of Alzheimer's disease and current pharmacological therapy.
KEYWORDS: Pathogenesis, Alzheimer's disease, Medication, Multi-target ligands, Polypharmacological.
INTRODUCTION:
Early symptoms primarily include cognitive impairment, particularly memory loss. Early symptoms primarily include cognitive impairment, particularly memory loss4. Physical limitations, such as the inability to walk, sit, or eat, indicate that the disease has progressed to the later stages while cognitive function deteriorates. The hallmark features identified in the cortical and limbic parts of the brain that are associated with AD are intracellular neurofibrillary tangles and extracellular amyloid plaques5.
Current Alzheimer's disease treatment can be divided into two categories based on the stage of the disease. Galantamine, rivastigmine, and donepezil as acetylcholinesterase inhibitors are suitable for mild to moderate cases to provide transient symptomatic relief among patients6. Memantine, an N-methyl D-aspartate (NMDA) antagonist, is used as a monotherapy to treat the symptoms of moderate to severe Alzheimer's disease. These medications are primarily selective molecules that target individual proteins ("one compound-one target" method), and they are mostly aimed at restoring physiological acetylcholine levels. Nonetheless, multiple pathways of Alzheimer's disease pathogenesis have been hypothesized to far, and they have been proven to overlap and influence one another7. This complexity calls into question the traditional single-target approach to treating Alzheimer's disease. Indeed, it is commonly acknowledged that the traditional single-target approach may not be sufficiently successful against AD, which has a multifactorial origin comprising a combination of genetic, metabolic, and environmental variables8. As a result, in recent decades, multi-target therapies have been widely explored as alternate choices for the management of multifactorial AD. Combination therapy based on a "cocktail medication-multiple targets" approach combining numerous pharmaceuticals working independently on separate targets, such as a pharmacological combination consisting of memantine and donepezil, have been used clinically to control the symptoms of moderate to severe AD9-10.
METHODS:
Pathogenesis of AD:
Because Alzheimer's disease is a complicated and multifaceted condition, establishing effective therapy regimens requires a thorough understanding of the disease's pathophysiology. The presence of extracellular beta amyloid (A) plaques in multiple parts of the AD patient's brain characterizes the majority of early-onset, autosomal dominant AD cases, owing to either overproduction or poor clearance of A peptides, or both. According to research, amyloid precursor protein (APP) is linked to the pathogenesis of Alzheimer's disease. A collection of enzymes termed as APP secretases, including -secretases, -secretases, and -secretases, work together in the brain to process the APP11. The -secretases in the physiological pathway digest the APP and create soluble APP (sAPP), which can prevent the subsequent -secretase activity. Soluble APP has been proven to be neuroprotective, allowing normal synaptic transmission and maintaining neural plasticity. In the amyloidogenic pathway, on the other hand, the -secretases, or BACE-1, produce soluble APP (sAPP-) and a short carboxy (C)-terminal fragment (CTF), which are both cleaved by the -secretases into insoluble and neurotoxic A peptides. A40 and A42 are the two major types of A peptides generated in AD, with 40 and 42 amino acid residues, respectively12. These A peptides aggregate to create oligomers of A (oA), which aggregate further to form insoluble amyloid plaques or senile plaques. The expression of the apolipoprotein E4 (APOE4) gene has been identified to be a factor that contributes to the pathogenesis of sporadic or late-onset Alzheimer's disease. According to research, people who express APOE4 have an increase in beta-amyloid deposition as well as decreased memory13-15.
Current Alzheimer's Disease Drug Therapies:
So far, research on Alzheimer's disease has advanced understanding of the illness's pathophysiology. Nonetheless, the Food and Drug Administration (FDA) has approved only a handful drugs to treat the condition. These drugs are primarily used to alleviate the symptoms of Alzheimer's disease, such as cognitive and global functioning; they are unable to slow the progression of the disease or treat its underlying causes. There are currently five basic pharmacotherapies for Alzheimer's disease based on two pharmacological classes: AChE inhibitors (rivastigmine, donepezil, galantamine) and NMDA receptor antagonists (memantine), as well as a combination therapy of an acetylcholinesterase inhibitor and memantine16-18.
As Alzheimer's disease advances, multiple therapeutic techniques are required to interfere in the underlying sub-pathologies. Primary prevention, secondary prevention, and symptomatic treatment are the three main stages of intervention depending on the course of AD19. Primary prevention therapies include those that target risk factors such as hypertension, diabetes, and dyslipidemia, which can result in pathophysiological alterations such as A plaque development. Secondary prevention involves medications that target A and Tau pathology or neuroinflammation; AD patients at this stage have the key markers of AD, such as A and tau aggregates or neuroinflammation, even if cognitive function is preserved. Finally, symptomatic treatment focuses on patients with poor cognition, and drugs that target altered neurotransmission, such as AChE inhibitors and NMDA antagonists, are useful. It is therefore critical to target the AD sub-pathologies that occur concurrently, especially if simultaneous targeting by a polypharmacological ligand is desired. There are three techniques to developing polypharmacological ligands: knowledge-based/medicinal chemistry-based, biological screening-based, and virtual screening-based. The majority of polypharmacological ligands are created using knowledge-based/medicinal chemistry-based methodologies that draw on existing medications' biological data from literature or commercial sources. Under this technique, polypharmacological ligands are divided into three types: conjugate, fused, and merged ligands20-22.
Donepezil:
The first-line treatment for Alzheimer's disease, is a second-generation AChE inhibitor, along with rivastigmine and galantamine23. It is a highly selective, reversible, and non-competitive AChE inhibitor with a slow gastrointestinal absorption and a relatively long half-life (50 to 70h). It works by increasing the concentration of acetylcholine in the hippocampus's synaptic cleft by inhibiting AChE and stimulating brainstem reticular formation, which leads to an increase in hippocampal theta rhythm amplitude. Donepezil was licensed for treatment in mild to moderate Alzheimer's disease in China in 2006, and for severe Alzheimer's disease in 201724. A researcher found that there was considerable improvement on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) scores at all time periods in research with 603 individuals. One study was conducted another 12-week, randomized, international research that included 111 individuals with mild to moderate Alzheimer's disease. The study regularly shown comparable improvement in ADAS-cog scores25.
Galantamine:
It is a dual-action drug that is both an acetylcholinesterase inhibitor and a positive allosteric modulator of nicotinic receptors. Previously conducted a study on the long-term effect of galantamine medication in 280 Alzheimer's disease patients26. The study found significant improvement in cognitive evaluation (based on MMSE and ADAS-cog scores, with a mean change from baseline of 2.6 and 5.6 points, respectively, after three years of galantamine administration). This was much better than the projected annual fall in scores in both parameters for untreated patients (2 to 4 points in MMSE and 6.7 points in ADAS-cog)27.
Rivastigmine:
It is another acetylcholinesterase inhibitor used to treat Alzheimer's disease. Unlike donepezil and galantamine, which inhibit only AChE, rivastigmine operates in the brain by inhibiting both AChE and butyrylcholinesterase (BuChE)28. It has little protein binding and so has little possibility for interaction with other pharmaceuticals; this makes it a better medication for the elderly who take multiple medications at the same time. When compared to the placebo group, a high dose of rivastigmine (6-12 mg/day) demonstrated considerable improvement in terms of ADAS-cog, global function, and progressive deterioration scale (PDS) scores in AD patients, according to Rösler et al. More patients in the higher dose group (24%) improved by 4 points or more29.
Memantine:
Aside from AChE inhibitors, memantine is another medication approved to treat the symptoms of Alzheimer's disease. It is a non-competitive voltage-dependent NMDA receptor antagonist that selectively binds to NMDA receptor-operated calcium channels30. Activation of synaptic NMDA receptors causes plasticity and increases neuronal cell survival under normal conditions. Excessive NMDA receptor activity, on the other hand, is harmful because it can promote cell excitotoxicity31. When this happens, the neuronal cells die, resulting in neurological dysfunction. Memantine suppresses the effects of over activated NMDA receptors, lowering neuronal cell death and preventing neuronal damage32-35.
CONCLUSION:
The findings of this systematic review indicate that using Another multi-target technique with a "one compound-multiple targets" approach has evolved as a polypharmacological therapy for Alzheimer's disease. A single medication molecule is developed to target two or more particular proteins involved in the development of AD in this strategy. When opposed to several medications delivered in combination, a single ligand can benefitly minimize adverse effects from drug interactions in combination therapy with a more predictable pharmacokinetic profile. Furthermore, it can improve patient compliance with straightforward dose schedules. As a result, multi-target medicines may constitute a viable alternative to the combination treatment therapeutic regimen in managing disease progression. The pathophysiology of Alzheimer's disease and current pharmacological therapy are covered in the following sections. Furthermore, multi-target treatments based on polypharmacological ligands for the condition are being developed36-37.
CONFLICT OF INTEREST:
The author has no conflicts of interest.
ACKNOWLEDGMENTS:
The author would like to thank NCBI, PubMed and Web of Science for the free database services for their kind support during this study.
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Received on 26.12.2022 Modified on 13.04.2023
Accepted on 29.07.2023 ©A&V Publications All right reserved
Res. J. Pharmacology and Pharmacodynamics.2024;16(1):48-51.
DOI: 10.52711/2321-5836.2024.00009