Nicotinic alpha 7 receptor agonists EVP-6124 and BMS-933043, attenuate scopolamine-induced deficits in visuo-spatial paired associates learning
Open accessAbstract
Agonists at the nicotinic acetylcholine alpha 7 receptor (nAChR α7) subtype have the potential to treat cognitive deficits in patients with Alzheimer's disease (AD) or schizophrenia. Visuo-spatial paired associates learning (vsPAL) is a task that has been shown to reliably predict conversion from mild cognitive impairment to AD in humans and can also be performed by nonhuman primates. Reversal of scopolamine-induced impairment of vsPAL performance may represent a translational approach for the development of nAChR α7 agonists. The present study investigated the effect of treatment with the acetylcholinesterase inhibitor, donepezil, or three nAChR α7 agonists, BMS-933043, EVP-6124 and RG3487, on vsPAL performance in scopolamine-treated cynomolgus monkeys. Scopolamine administration impaired vsPAL performance accuracy in a dose- and difficulty- dependent manner. The impairment of eventual accuracy, a measure of visuo-spatial learning during the task, was significantly ameliorated by treatment with donepezil (0.3 mg/kg, i.m.), EVP-6124 (0.01 mg/kg, i.m.) or BMS-933043 (0.03, 0.1 and 0.3 mg/kg, i.m.). Both nAChR α7 agonists showed inverted-U shaped dose-effect relationships with EVP-6124 effective at a single dose only whereas BMS-933043 was effective across at least a 10 fold dose/exposure range. RG3487 was not efficacious in this paradigm at the dose range examined (0.03-1 mg/kg, i.m.). These results are the first demonstration that the nAChR α7 agonists, EVP-6124 and BMS-933043, can ameliorate scopolamine-induced cognitive deficits in nonhuman primates performing the vsPAL task.
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Accumulating evidence from preclinical studies suggests that activation of α7-nAChR signalling results in suppression or prevention of anxiety.
“Accumulating evidence from preclinical studies suggests that activation of α7-nAChR signalling results in suppression or prevention of anxiety. 20–22”
From Efficacy and safety of an alpha 7-nicotinic acetylcholine receptor agonist, VQW-765, in subjects with performance anxiety: randomised, double-blind, placebo-controlled trial (2025) · cites this paper as [22]
The Introduction describes preclinical improvements in attention and memory, and the Discussion describes pro-cognitive effects of α7-nAChR agonists (page numbers unavailable). Searches for anxiety, anxiolytic effects, and anxiety-like behavior found no passage addressing suppression or prevention of anxiety. (LLM, conf=0.72)
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- Authors
- Weed, M. R., Polino, J., Signor, L., Bookbinder, M., Keavy, D., Benitex, Y., Morgan, D. G., King, D., Macor, J. E., Zaczek, R., Olson, R., & Bristow, L. J.
- Affiliations
- Bristol-Myers Squibb (United States) (US)
- Corresponding author
- Weed, Michael R.
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2017-12-19
- Volume
- 12
- Issue
- 12
- Pages
- e0187609
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC5736175
- OpenAlex
- W2777005829
- Cited by
- 13
- References
- 60
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 3 · 2019: 3
- FWCI
- 0.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Bristol-Myers Squibb
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- scopolamine-induced cognitive deficits, donepezil, acetylcholinesterase inhibitors, Alzheimer's disease, mild cognitive impairment, Macaca fascicularis, dose-response relationship, cognitive enhancement
- MeSH terms
- Donepezil, Animals, Indans, Macaca fascicularis, Male, Paired-Associate Learning, Piperidines, Quinuclidines, Reaction Time, Scopolamine, Space Perception, Spiro Compounds, Task Performance and Analysis, Thiophenes, Visual Perception, Treatment Outcome, alpha7 Nicotinic Acetylcholine Receptor
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