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Current Topics in Medicinal Chemistry

ISSN: 1568-0266 eISSN: 1873-5294

BENTHAM S C I E N C E The international

journal for in-depth reviews on Current Topics in

Medicinal Chemistry Impact Factor:2.9

Badar ul Islam

¹

, Mohd Shahnawaz Khan

²

, Nasimudeen R. Jabir

³

, Mohammad Amjad Kamal

^3,4,5

and Shams Tabrez

^3,*

1

Department of Biochemistry, J. N. Medical College, Faculty of Medicine, Aligarh Muslim University, Aligarh 202002, India;

²

Protein Research Chair, Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia;

³

King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia;

⁴

Enzymoics;

5

Novel Global Community Educational Foundation, 7 Peterlee Place, Hebersham, NSW 2770, Australia

A R T I C L E H I S T O R Y

Received: July 04, 2016 Revised: August 08, 2016 Accepted: August 09, 2016

DOI: 10.2174/15680266176661701031 63715

Abstract: Alzheimer’s disease (AD) is an irreversible multifaceted neurodegenerative disorder that

gradually degrades neuronal cells. Presently, it is the most common reason for the memory loss and dementia in older individuals. It is patho-physiologically described by extracellular amyloid beta (Aβ) deposition, intracellular neurofibrillary tangles (NFTs) retention, neuronal decline, and neurotransmit- ter system derangement. Various receptors such as nicotinic acetylcholine, N-methyl-D-aspartate, in- sulin, serotonin, adenosine, and histamine are actively involved in the physiological progression of AD. Till date memantine and only four other acetylcholinesterase inhibitors have been approved for the treatment of AD by US Food and Drug Administration (US-FDA). Hence, there is a critical need to explore and develop novel and helpful management systems which could specifically target differ- ent receptors involved in AD progression. We believe that these receptors targeting will either impede the disease onset or slow down its pathogenesis. In the present review, we tried to uncover some re- ceptors that could be blocked by novel inhibitors and ultimately used for the therapeutic management of AD.

Keywords: Alzheimer’s disease, Nicotinic acetylcholine receptors, N-methyl-D-aspartate receptor, Insulin receptor, Adenosine receptor.

INTRODUCTION

The studies on Alzheimer’s disease (AD) gained interest among researchers for the past several years due to its worldwide etiology [1]. It is the most common form of dementia characterized by neuronal dysfunction and apoptosis that results in memory decline and impaired cognitive functions [2]. Around 36 million people are affected by this disorder [3] and this number is expected to increase upto 114 million by 2050 [4]. Alzheimer’s disease is categorized into early onset or familial AD (1-6%) and sporadic AD (>90%) [5]. Its multifaceted patho-physiology includes enhanced retention of amyloid beta (Aβ) plaque around neuronal cells and neurofibrillary tangles formed by hyper-phosphorylated tau-related microtubule inside cells [6, 7]. Some other disturbed mechanisms like calcium release, persistent oxidative imbalance, mitochondrial and mitotic dysfunction, hormone disparity and inflammation also participate in AD pathogenesis. The proteasome system is the main clearance ma- chinery for hyper-phosphorylated tau but this system is blocked by Aβ oligomers and plaques [8]. As a result of it, the intracellular Ca

²⁺

concentration gets disturbed [9] and activates different inflammatory cascades [10], thereby

*Address correspondence to this author at the King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia; E-mail: [email protected]

promotes neuronal dysfunction. Various hypotheses for AD pathogenesis have been put forwarded by the neuroscientists that include amyloid formation [11], glutamate-mediated or glutamatergic [12], oxidative imbalance [13], inflammatory- mediated [14], acetylcholine-mediated or cholinergic [15]

and finally metal-based [16].

Till date, memantine, and only four other cholinesterase blockers are approved by the US-FDA for AD management.

However, these drugs are unable to divert route of the disease rather they just provide symptomatic effects. Therefore, the need of hour is to find out novel and sophisticated therapeutic alternatives that could target the complex mechanisms involved in AD progression. In the present review, we focus on the different receptors that could be potentially targeted for the therapeutic approaches in AD treatment and offers clinical perspectives in deciphering the mysteries of AD puzzle. The different receptors targeting for AD treatment is schematically outlined in Fig. (1). In the following section, we will try to uncover various receptor based therapeutics that could give the positive outcome in terms of AD management and its treatment.

NICOTINIC ACETYLCHOLINE RECEPTORS (nAChRs):

Cholinergic neurons are widespread in the dense nuclei across central nervous system (CNS). Anatomical studies demonstrated substantial loss of brain white matter and

Current Topics in Medicinal Chemistry, 2017, 17, 1400-1407

REVIEW ARTICLE

Elucidating Treatment of Alzheimer’s Disease via Different Receptors

1873-529/17 $58.00+.00 © 2017 Bentham Science Publishers

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Fig. (1). Schematic outline of potential receptor targeting for AD therapeutic approaches.

decrease in cholinergic neurons residing in basal forebrain in AD [17, 18]. Acetylcholine (Ach) is a neurotransmitter, attached to two receptor families namely nicotinic acetylcholine receptors (nAChRs) and muscarinic acetylcholine receptors (mAChRs). Both types of receptors are suggested to control the cognitive processes and are influenced in AD [19]. Nicotinic acetylcholine receptors are transmembrane pentameric proteins belonging to ligand-gated ion channel superfamily having Cys-loop that includes glycine, α-amino- 3-hydroxy-5-methyl-4-isoxazolepropionic acid GABA

_A

, GABA

C

and 5-hydroxytryptamine (5-HT3) receptors and play important roles in neuronal excitability and release of neurotransmitters [20-22]. The α4β2 is the major nAChR receptor subtype in the brain (almost 90%) [23, 24] whereas, α3β4 nAChR subtype is mainly found in the peripheral nerv- ous system and also expressed in other brain parts [25].

The localization of α7 nAChR subunit is quite widespread ranging from immune cells [25, 26], neurons [27] and other regions of brain. They participate in learning and memory [28, 29]. These receptors are highly permeable to calcium that helps in the release of neurotransmitters from presynaptic terminals [30, 31] and modulation of intracellular signaling [32]. Studies on the expression of α7 subunit receptors in non-neuronal cells implicate their role in brain inflammation, innate immunity, and neuroprotection [33, 34]. Recent studies reported a novel α7β2 nAChR subtype (sensitive to Aβ-induced toxicity) in cholinergic neurons of forebrain and interneurons of hippocampus in mouse brain and also in human basal forebrain [35, 36]. The kinetics and permeability of nAChR channel are directly governed by the composition of subunits. This characteristic of nAChR subtype in brain determines particular brain disorder. Hence, α7 and non-α7 nAChR subtypes are considered as potential therapeutic targets in chronic pain, neuro-developmental diseases, and neurodegenerative disorders. Several studies demonstrated the interaction of α7 nAChRs with Aβ and its consequences [37-39]. We have also depicted this interaction and their possible outcome with the help of a cartoon in Fig.

(2). One of the strategies for AD treatment via nAChR is the use of nAChR agonists that interfere the interaction between nAChR and Aβ. A partial nAChR agonist, 2-[2-(4- bromo- phenyl)-2-oxoethyl]-1-methyl pyridinium (S 24795), sepa- rate Aβ in a dose-dependent manner when applied to synap- tosomal complexes prepared from rat frontal cortex and human AD samples after post mortem. It also normalizes Ca

²⁺

influx induced by N-methyl-D-aspartate glutamate receptor and nAChR [39, 40]. Another partial choline agonist has been reported for an analgesic effect in rodent pain models [41]. A scientific study involving APP

_swe

mice demonstrated

the decrease in Aβ deposition in blood vessels along with a rise in α7 nAChR population in response to nicotine admini- stration [42]. On the other hand, another study on AD model 3xTg-AD reported, rapid formation of tau aggregates in CA1 pyramidal neurons after long-term nicotine exposure, proba- bly due to the enhancement of tau aggregates by nicotine involving p38-MAP kinase activation [43]. Despite its role in reducing plaque load, nicotine administration should be checked owing to its toxicity on tau pathology. Moreover, cotinine (the metabolite of nicotine) has been reported for its beneficial effects on attention and memory with lesser toxic- ity [44] and also reported to reduce the plaque load via Akt pathway activation [45]. Another agonist, 4OH-GTS-21, has been reported to restore spatial memory without affecting neuronal density in mice model [46, 47].

Pregnenolone sulfate (PREGS) is an endogenous steroid that improves cognitive performance and modulates synaptic plasticity via glutamatergic transmission [48]. The administration of PREGS in the mouse model has been reported to improve spatial memory and reduces apoptosis in CA1 pyramidal cells, but their role in α7 nAChR activation is not clear [49]. Moreover, commonly used statin and simvastatin are reported to have beneficial effect in improving cognitive function in AD patients [50]. Apart from these, another approach is the intracellular signaling pathway involving the interaction of Aβ to nAChR at cell surfaces aided by filamin A (FLNA) [51]. Administration of PTI-125 averted the interaction of FLNA with α7 and leads into affinity reduction of Aβ for nAChR, and ultimately reduces Aβ toxicity [52].

There are other partial agonists that are in clinical trials namely EVP-6124 or MT-4666, varenicline (partial agonist for α4β2 and full agonist at α7 nAChRs) and AZD-3480 (partial agonist for α4β2 and α2β2 nAChR) [53, 54]. Differ- ent agonists stimulate the receptor present on the surface of the cell whereas scaffold proteins attached nicotinic receptors modulate intracellular signal transduction. This protein- receptor interaction is the main event that has to be targeted for the research and prospective treatment of neurodegenerative disorders like AD.

N-METHYL-D-ASPARTATE (NMDA) RECEPTORS N-methyl-D-aspartate (NMDA)-kind glutamate receptors are involved in the neuronal pathology of AD at late disease stage. The excessive activation of these receptors results in the increased Ca

²⁺

influx via receptor-linked ion channel in AD patients [55]. Glutamate-modulated synaptic conduction is essential for proper functioning of nervous system. The

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Fig. (2). The interaction of α7 nAChRs with Aβ and its consequences.

associated neurons modulate cognition, synaptic plasticity, learning and memory, proper neuronal growth, and differen- tiation [56, 57]. The glutamate cycle modulation in AD cause the accumulation of glutamate that results in over- activation of NMDA receptors and leads to neuronal cell death through free radical damage [58]. The improper glutamate release disrupts energy to process. Neurons in this state are unable to sustain ionic homeostasis, thereby causing the release of Mg

²⁺

and inhibits NMDA receptor-linked channels [59]. NMDA receptor is composed of tetrameric subunits (NR1 and NR2A-D, NR3A or B in some cases). This subunit composition is vital for the characteristics of receptor-linked ion channel complex [60]. Hence, antagonists for NMDA receptors could be therapeutically used against neurodegen- erative disorders like AD [61]. The only available NMDA receptor antagonist is memantine (uncompetitive), that has high voltage and fast blocking activity, impede the receptor- linked channel in open conformation [62-63]. However, re- cent report suggests non-effectiveness of memantine for the treatment of cognitive disorders of multiple sclerosis [64].

Lately, several docking studies discovered active potential ligands against NMDA receptor in AD. The key ligands identified by molecular docking are 1-benzyl-1,2,3,4- tetrahydro-b-carboline [65], derivatives of 3-hydroxy-1H- quinazoline-2,4-dione [66], triazolylamidine and phenyla- midine [67], 3-substituted-1H-indoles etc [68].

INSULIN RECEPTORS

Insulin and insulin-like growth factors (IGF) regulate different neuronal functions ranging from growth to metabolism. The impaired insulin-induced signaling adversely af- fects brain along with disturbances in glucose homeostasis, energy consumption, abrupt amyloid precursor protein processing, tau hyper-phosphorylation, oxidative stress and mito-

chondrial dysfunction [69]. The lack of marginal insulin resistance leads to a considerable decrease in the expression of insulin and IGF along with their receptors in AD [70]. A recent study demonstrated that elevated level of IGF-1 may provide protection against subclinical and clinical neurode- generation [71]. Moreover, the increased expression of insulin-like growth factor binding protein 3 (IGFBP-3) results in tau phosphorylation and Aβ-mediated cell death [72]. Re- cently, a meta-analysis study also highlighted the potential of IGF and IGFBP-3 in AD treatment [73]. Based on these facts, it has been suggested that raising insulin sensitivity in the brain and blockers of IGFBP-3 might have beneficial effect on brain functions. One of the insulin receptor agonists is rosiglitazone that mediates insulin sensitization, but reports from clinical trials in AD patients are not encouraging [74].

SEROTONIN RECEPTORS

Various serotonin receptors namely 5-HT

1A

, 5-HT

4

, 5- HT

₆

and 5-HT

₇

are present in high density in the brain sec- tions associated with memory and learning [75, 76]. The 5- HT

_1A

receptors are expressed at pre- and post-synaptic areas [77]. At pre-synaptic region, 5-HT

1A

auto-receptors nega- tively check serotonin-mediated transmission while on the contrary, at the post-synaptic region, acetylcholine-mediated transmission is hindered by 5-HT

_1A

activation. Moreover, the elevated concentrations of 5-HT

4

and 5-HT

6

receptors are detected in both basal ganglia and hippocampus [78, 79].

King et al. [79] suggested that various other neurotransmitter systems are modulated by serotonin system because of 5-HT receptors co-localization on acetylcholine, GABA and glutamate-mediated neurons [79]. Several antagonistic or ago- nistic ligands for 5-HT receptors have been also reported in literature [79]. Moreover, various serotonin mimics, such as

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Table 1. Receptor based inhibitors in Alzheimer’s treatment and their current status.

Name of inhibitor Type of receptor Mechanism of action Current status Reference

S 24795 nAChR Partial receptor agonist Preclinical stage [39, 40]

4OH-GTS-21 nAChR Receptor agonist Preclinical stage [46, 47]

Pregnenolone sulfate nAChR Glutamatergic transmission Preclinical stage [48]

PTI-125 nAChR Inhibits interaction between FLNA and α7 Preclinical stage [52]

EVP-6124 or MT-4666 nAChR Partial receptor agonist Clinical trial [53]

Varenicline α4β2 and α7 nAChR Partial and full receptor agonist Clinical trial [54]

Memantine NMDAR Uncompetitive receptor antagonist FDA approved [63]

1-benzyl-1,2,3,4-tetrahydro-b-

carboline NMDAR Receptor antagonist Preclinical stage [65]

Triazolylamidine NMDAR Receptor antagonist Preclinical stage [67]

Rosiglitazone IGF Insulin sensitization Clinical trial [74]

Lecozotan 5-HT1A Receptor antagonist Clinical trial [81]

Velusetrag, RQ-00000009, PRX- 03140, SUVN-D1003019, SUVN-

1004028 and TD-8954

5-HT4 Receptor agonist Clinical trial [82]

SB-399885, Ro-4368554, SB-

258585 5-HT6 Receptor antagonist Preclinical stage [83, 84]

Propentofylline Adenosine receptor Non-selective blocker Preclinical stage [93, 94]

SCH58261 A2A Receptor blocker Preclinical stage [95]

GSK189254, PF-03654746, ABT-

288, MK-0249 and BF2.649 H3 Receptor antagonist Clinical trial [99-102]

nAChR: Nicotinic acetylcholine receptor NMDA: N-methyl-D-aspartate receptor

inhibitors of monoamine oxidase and partial serotonin reup- take are already therapeutically used and are in consideration for AD therapy [77, 80]. Lecozotan, 5-HT

_1A

antagonist, is reported to be safe and effective in clinical trials [81]

whereas 5-HT

4

agonists are velusetrag, RQ-00000009, PRX- 03140, SUVN-D1003019, SUVN-1004028 and TD-8954 and exhibit amyloid processing potential [82]. Different 5- HT

₆

agonists (SB-742457) and antagonists (SB-399885, Ro- 4368554 and SB-258585) reported to have cognition- boosting properties [83, 84]. Therefore, additional studies are required to decipher their mechanism of action in AD therapy.

ADENOSINE RECEPTORS

There are four adenosine receptors namely A1, A2A, A2B, and A3. Out of these four, A1 and A2A are present at high density in the brain and participate in the proper functioning of neurons connecting to AD-mediated cognitive disorders [85, 86]. Scientific reports suggest that both localization and density of adenosine receptors are perturbed in AD brain [87, 88]. Persistent stressful state in brain stimu- lates the A2A expression implying the assumption that manipulation of these receptors might be helpful in the management of neuro-degenerative disorder [89, 90]. Conse-

quently, various studies demonstrated AD management via A2A manipulation [86, 91]. The safe doses of caffeine are one of the antagonistic blockers of A1 and A2A and showed beneficial effects [92]. Another compound propentofylline, non-selective blocker of adenosine receptors and nucleoside transporters, also showed effects on cognition but not in patients having vascular dementia [93, 94]. SCH58261 (A2A blocker) displayed neuroprotective function whereas combi- nation therapy of antiplatelet drug, cilostazo, and PDE-3 inhibitor showed beneficial effects in dementia [95]. Hence, A2A inhibition may be a novel prophylactic and/or therapeutic approach to manage AD but more in-depth studies are required for the identification of novel ligands that inhibit adenosine receptors only.

HISTAMINE RECEPTORS

Expression of histamine receptors especially H3 is quite high in brain areas associated with cognitive functions and sleep-wake processes [96]. H3 is a G-protein coupled receptor with constitutive activity of auto-signal property. In the brain, histamine flow is hampered by the activated receptor via adenylate cyclase/protein kinase A along with Ca

²⁺

/calmodulin-dependent protein kinase II pathways [97].

The compounds having selective antagonistic properties in-

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duce several other neurotransmitters like GABA, acetylcholine, noradrenaline and dopamine. Medhurst et al. [98] reported that the expression of H3 receptor is unaffected re- gardless of AD progression, which highlights the potential of H3 receptor as a therapeutic approach. Scientific studies reported new H3 antagonists viz, GSK189254, PF-03654746, ABT-288, MK-0249 and BF2.649 which showed increased cognition [99]. ABT-288 and GSK239512 are reported to be safe and displayed beneficial effects on memory and attention [100, 101]. On the other hand, MK-0249 did not show any assistance in early AD patients [102]. The mechanism of action of these compounds are still not clear and further comprehensive studies are required to decipher their mechanism. To summarize our manuscript, we have provided various receptor based inhibitors, their mechanism of action and current status in Table (1).

FUTURE PERSPECTIVES AND CONCLUSION Although, the drug industry is pouring billions into R&D against AD but the success rate of these drug in clinical trial are disappointing. The reason behind the failure is due to complex nature of brain and our inability to correctly under- stand the mechanism of AD patho-physiology. On the basis of current knowledge, it is quite clear that the control of cognitive deficit should be main goal of AD treatment. To achieve this objective, the potential treatment method should be based on proteins, genes or stem cells. Recently, Suber- bielle et al. [103] reported that pathological accumulation of Aβ, might promote the proteasomal degradation of BRCA1 through over-activation of extra-synaptic NMDA receptors.

Their study highlight the potential of BRCA1 inhibitor that could be used for effective treatment of AD. Some of the BRCA1 inhibitors that are at late stage of clinical trial for cancer treatment viz. Olaparib, Veliparib, Talazoparib, Niraparib and Rucaparib could be tried for AD management [104] as well. Moreover, ApoE genotyping could also be the part of prevention and early reversal of AD symptoms [105].

It is also well known that amyloid plaques are associated with inflammation which are duly taken care off by stem cells infusion (very effective anti-inflammatories). We believe that stem cells infusion could also be one of option to improve AD condition.

To summarize our article, it is quite clear that receptor mediated therapeutic targeting has significant potential in AD management. However, further rigorous studies are required that could provide a certain novel compound/s, which does not only help in symptomatic treatment rather control or slow down the relentless progression of AD.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

The authors gratefully acknowledge the research facility provided by the Aligarh Muslim University, Aligarh, India and King Fahd Medical Research Center (KFMRC), King Abdulaziz University, Jeddah, Saudi Arabia. Thanks are also due to Mohammad S Gazdar (Librarian, KFMRC) for pro- viding assistance with the literature.

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