The current agonists and positive allosteric modulators of α 7 nAChR for CNS indications in clinical trials

Yang, Taoyi; Xiao, Ting; Sun, Qi; Wang, Kewei

doi:10.1016/j.apsb.2017.09.001

Cited by 97 publications

(94 citation statements)

References 156 publications

(190 reference statements)

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“…Drugs displaying disease‐modifying properties are still not available for AD. Improving the function of the α7nAChR has gained increasing interest in this context with several drug candidates having been developed or currently under development to treat AD symptoms (Bertrand & Terry, ; Yang et al, ). Aβ, an important component of AD development, is known to impact on the function of the α7nAChR although the precise functional effect of Aβ on α7nAChRs is still a matter of debate.…”

Section: Discussionmentioning

confidence: 99%

“…The α7nACh receptor is involved in learning and memory processes by inducing LTP, and its function is altered in the course of AD pathology (Bertrand, Lee, Flood, Marger, & Donnelly-Roberts, 2015;Gotti et al, 2006). Accordingly, restoring its activity has been proven beneficial in a variety of experimental models as well as in clinical trials (Ma et al, 2014;Thomsen, Hansen, Timmerman, & Mikkelsen, 2010;Yang, Xiao, Sun, & Wang, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Quantitative assessment of oligomeric amyloid β peptide binding to α7 nicotinic receptor

Cecon

Dam

Luka

et al. 2019

British J Pharmacology

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Background and Purpose Progressive dysfunction of cholinergic transmission is a well‐known characteristic of Alzheimer's disease (AD). Amyloid β (Aβ) peptide oligomers are known to play a central role in AD and are suggested to impair the function of the cholinergic nicotinic ACh receptor α7 (α7nAChR). However, the mechanism underlying the effect of Aβ on α7nAChR function is not fully understood, limiting the therapeutic exploration of this observation in AD. Here, we aimed to detect and characterize Aβ binding to α7nAChR, including the possibility of interfering with this interaction for therapeutic purposes. Experimental Approach We developed a specific and quantitative time‐resolved FRET (TR‐FRET)‐based binding assay for Aβ to α7nAChR and pharmacologically characterized this interaction. Key Results We demonstrated specific and high‐affinity (low nanomolar) binding of Aβ to the orthosteric binding site of α7nAChR. Aβ binding was prevented and reversed by the well‐characterized orthosteric ligands of α7nAChR (epibatidine, α‐bungarotoxin, methylylcaconitine, PNU‐282987, S24795, and EVP6124) and by the type II positive allosteric modulator (PAM) PNU‐120596 but not by the type I PAM NS1738. Conclusions and Implications Our TR‐FRET Aβ binding assay demonstrates for the first time the specific binding of Aβ to α7nAChR, which will be a crucial tool for the development, testing, and selection of a novel generation of AD drug candidates targeting Aβ/α7nAChR complexes with high specificity and fewer side effects compared to currently approved α7nAChR drugs. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Quantitative assessment of oligomeric amyloid β peptide binding to α7 nicotinic receptor

Cecon

Dam

Luka

et al. 2019

British J Pharmacology

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“…In fact, when consulting some reviews that provide intense detail about the various modulators of α7 nAChR, we observed that the modulators that interact with these receptors by an allosteric mechanism are in smaller proportion relative to regular agonists. Interestingly, these compounds may interact with α7 nAChR either as positive or negative allosteric modulators (PAMs or NAMs).…”

Section: Nicotinic Acetylcholine Receptors (Nachrs)mentioning

confidence: 98%

“…α7 nAChR is present on synaptic regions and is therefore directly related to neurotransmission. For instance, ACh, as its natural agonist, activates this receptor for signaling in the synapse . This receptor also plays a role in delivering glutamate to the cerebellum and hippocampus, and it also may be capable of interacting with Aβ peptide .…”

Section: Nicotinic Acetylcholine Receptors (Nachrs)mentioning

confidence: 99%

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Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review

et al. 2019

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Among neurodegenerative disorders, Alzheimer's disease (AD) is the most common type of dementia, and there is an urgent need to discover new and efficacious forms of treatment for it. Pathological patterns of AD include cholinergic dysfunction, increased β‐amyloid (Aβ) peptide concentration, the appearance of neurofibrillary tangles, among others, all of which are strongly associated with specific biological targets. Interactions observed between these targets and potential drug candidates in AD most often occur by competitive mechanisms driven by orthosteric ligands that sometimes result in the production of side effects. In this context, the allosteric mechanism represents a key strategy; this can be regarded as the selective modulation of such targets by allosteric modulators in an advantageous manner, as this may decrease the likelihood of side effects. The purpose of this review is to present an overview of compounds that act as allosteric modulators of the main biological targets related to AD.

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Targeted therapy with galantamine in a pediatric patient with 15q13.3 deletion syndrome

Casas‐Alba

Nolasco

Díez-Juan

et al. 2021

American J of Med Genetics Pt A

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The current agonists and positive allosteric modulators of α 7 nAChR for CNS indications in clinical trials

Cited by 97 publications

References 156 publications

Quantitative assessment of oligomeric amyloid β peptide binding to α7 nicotinic receptor

Quantitative assessment of oligomeric amyloid β peptide binding to α7 nicotinic receptor

Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review

Targeted therapy with galantamine in a pediatric patient with 15q13.3 deletion syndrome

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