CoChat
Sign Up
Cited by 30Nicotinic Acetylcholine Receptors StudySchizophrenia research and treatmentNeuroscience and Neuropharmacology Research

The Novel, Nicotinic Alpha7 Receptor Partial Agonist, BMS-933043, Improves Cognition and Sensory Processing in Preclinical Models of Schizophrenia

Open access
Bristow, Linda J., Easton, Amy E., Li, Yu-Wen, Sivarao, Digavalli V., Lidge, Regina, Jones, Kelli M., Post-Munson, Debra, Daly, Christopher +15 more·2016·PLOS ONE
DOI 10.1371/journal.pone.0159996PMC PMC4965148
Open this paper in CoChat — free account

Abstract

The development of alpha7 nicotinic acetylcholine receptor agonists is considered a promising approach for the treatment of cognitive symptoms in schizophrenia patients. In the present studies we characterized the novel agent, (2R)-N-(6-(1H-imidazol-1-yl)-4-pyrimidinyl)-4'H-spiro[4-azabicyclo[2.2.2]octane-2,5'-[1,3]oxazol]-2'-amine (BMS-933043), in vitro and in rodent models of schizophrenia-like deficits in cognition and sensory processing. BMS-933043 showed potent binding affinity to native rat (Ki = 3.3 nM) and recombinant human alpha7 nicotinic acetylcholine receptors (Ki = 8.1 nM) and agonist activity in a calcium fluorescence assay (EC50 = 23.4 nM) and whole cell voltage clamp electrophysiology (EC50 = 0.14 micromolar (rat) and 0.29 micromolar (human)). BMS-933043 exhibited a partial agonist profile relative to acetylcholine; the relative efficacy for net charge crossing the cell membrane was 67% and 78% at rat and human alpha7 nicotinic acetylcholine receptors respectively. BMS-933043 showed no agonist or antagonist activity at other nicotinic acetylcholine receptor subtypes and was at least 300 fold weaker at binding to and antagonizing human 5-HT3A receptors (Ki = 2,451 nM; IC50 = 8,066 nM). BMS-933043 treatment i) improved 24 hour novel object recognition memory in mice (0.1-10 mg/kg, sc), ii) reversed MK-801-induced deficits in Y maze performance in mice (1-10 mg/kg, sc) and set shift performance in rats (1-10 mg/kg, po) and iii) reduced the number of trials required to complete the extradimensional shift discrimination in neonatal PCP treated rats performing the intra-dimensional/extradimensional set shifting task (0.1-3 mg/kg, po). BMS-933043 also improved auditory gating (0.56-3 mg/kg, sc) and mismatch negativity (0.03-3 mg/kg, sc) in rats treated with S(+)ketamine or neonatal phencyclidine respectively. Given this favorable preclinical profile BMS-933043 was selected for further development to support clinical evaluation in humans.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1371/journal.pone.0159996

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Mask wearing has been reported to reduce social anxiety symptoms for individuals with SAD when interacting with others or performing in social situations.

    “Mask wearing has been reported to reduce social anxiety symptoms for individuals with SAD when interacting with others or performing in social situations. 28”

    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 [28]

    The Introduction discusses schizophrenia symptoms, and the Discussion reports effects of BMS-933043 in preclinical cognitive and sensory-processing models; neither addresses mask wearing or social anxiety disorder (SAD). Searches for mask wearing, SAD, and social situations returned no passage supporting the claimed symptom reduction. Page numbers were not provided in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

No citation lists for this paper

No citation lists for this paper yet — checked again daily.

References 49 · Cited by 30

Research works printed but not linked: 48

  1. [1]Fuller R, Nopoulos P, Arndt S, O’Leary D, Ho BC and Andreasen NC. Longitudinal assessment of premorbid cognitive functioning in patients with schizophrenia through examination of standardized scholastic test performance. Am J Psychiatry 2002; 159: 1183– 1189. 12091197
  2. [2]Green MF, Kern RS and Heaton RK. Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS. Schizophrenia Research 2004; 72: 41– 51. 15531406
  3. [3]Gold J. Cognitive deficits as treatment targets in schizophrenia. Schizophrenia Research 2004; 72: 21– 28. 15531404
  4. [4]Galletly C. Recent advances in treating cognitive impairment in schizophrenia. Psychopharmacology (Berl) 2009; 202: 259– 273. 18766331
  5. [5]Barik J and Wonnacott S. Molecular and cellular mechanisms of action of nicotine in the CNS. Handbook of Experimental Pharmacology 2009; 192: 173– 207. 10.1007/978-3-540-69248-5_7 19184650 · DOI
  6. [7]Papke RL. Merging old and new perspectives on nicotinic acetylcholine receptors. Biochem Pharmacol. 2014; 89: 1– 11. 10.1016/j.bcp.2014.01.029 24486571 PMC4755309 · DOI
  7. [8]Taly A, Corriger PJ, Guedin D, Lestage P and Changeux JP. Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system. Nature Reviews Drug Discovery 2009; 8: 733– 750. 10.1038/nrd2927 19721446 · DOI
  8. [9]Bitner RS, Bunnelle WH, Anderson DJ, Briggs CA, Buccafusco J, Curzon P et al Broad-spectrum efficacy across cognition domains by α7 nicotinic acetylcholine receptor agonism correlates with activation of ERK1/2 and CREB phosphorylation pathways. J Neurosci. 2007; 27: 10578– 10587. 17898229 PMC6673141
  9. [10]Biton B, Bergis OE, Galli F, Nedelec A, Lochead AW, Jegham S et al SSR180711, a novel selective alpha7 nicotinic receptor partial agonist: (1) binding and functional profile. Neuropsychopharmacology 2007; 32: 1– 16. 17019409
  10. [11]Duffy AM, Zhou P, Milner TA and Pickel VM. Spatial and intracellular relationships between the α7 nicotinic acetylcholine receptor and the vesicular acetylcholine transporter in the prefrontal cortex of rat and mouse. Neuroscience 2009; 161: 1091– 1103. 10.1016/j.neuroscience.2009.04.024 19374941 PMC2720620 · DOI
  11. [12]Lewis DA and Sweet RA. Schizophrenia from a neural circuitry perspective: advancing toward rational pharmacological therapies. J Clinical Investigation 2009; 119: 706– 715. PMC2662560 19339762
  12. [13]Zolles G, Wagner E, Lampert A and Sutor B. Functional expression of nicotinic acetylcholine receptors in rat neocortical layer 5 pyramidal cells. Cerebral Cortex 2009; 19: 1079– 1091. 10.1093/cercor/bhn158 18794204 · DOI
  13. [14]Livingstone PD, Srinivasan J, Kew JNC, Dawson LA, Gotti C, Moretti M et al α7 and non-α7 nicotinic acetylcholine receptors modulate dopamine release in vitro and in vivo in the rat prefrontal cortex. Eur J Neurosci. 2009; 29: 539– 550. 10.1111/j.1460-9568.2009.06613.x 19187266 · DOI · Paper page
  14. [15]Krenz I, Kalkan D, Wevers A, de Vos RA, Steur EN, Lindstrom J et al Parvalbumin-containing interneurons of the human cerebral cortex express nicotinic acetylcholine receptor proteins. J Chem Neuroanat. 2001; 21: 239– 246. 11382535
  15. [16]Macor JE, Gurley D, Lanthorn T, Loch J, Mack RA, Mullen G et al The 5-HT3 antagonist tropisetron (ICS 205–930) is a potent and selective alpha7 nicotinic receptor partial agonist. Bioorg Med Chem Lett. 2001; 11: 319– 321. 11212100
  16. [17]Hashimoto K, Fujita Y, Ishima T, Hagiwara H and Iyo M. Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of tropisetron: Role of α7 nicotinic receptors. Eur J Pharmacol. 2006; 553: 191– 195. 17094961
  17. [18]Wallace TL, Callahan PM, Tehim A, Bertrand D, Tombaugh G, Wang S et al RG3487, a novel nicotinic α7 receptor partial agonist, improves cognition and sensorimotor gating in rodents. J Pharmacol Exp Ther. 2011; 336: 242– 253. 10.1124/jpet.110.171892 20959364 · DOI
  18. [19]Jones KM, McDonald IM, Bourin C, Olsen RE, Bristow LJ and Easton A. Effect of alpha7 nicotinic acetylcholine receptor agonists on attentional set-shifting impairment in rats. Psychopharmacology (Berl) 2014; 231: 673– 683. 24057763
  19. [20]Hashimoto K, Ishima T, Fujita Y, Matsuo M, Kobashi T, Takahagi M et al Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the novel selective α7 nicotinic receptor agonist SSR180711. Biological Psychiatry 2008; 63: 92– 97. 17601496
  20. [21]Pichat P, Bergis OE, Terranova JP, Urani A, Duarte C, Santucci V et al SSR180711, a novel selective alpha7 nicotinic receptor partial agonist: (II) efficacy in experimental models predictive of activity against cognitive symptoms of schizophrenia. Neuropsychopharmacology 2007; 32: 17– 34. 16936709
  21. [22]Tietje KR, Anderson DJ, Bitner RS, Blomme EA, Brackemeyer PJ, Briggs CA et al Preclinical characterization of A-582941: a novel alpha7 neuronal nicotinic receptor agonist with broad spectrum cognition-enhancing properties. CNS Neurosci Ther. 2008; 14: 65– 82. 10.1111/j.1527-3458.2008.00037.x 18482100 PMC6494002 · DOI
  22. [23]Hauser TA, Kucinski A, Jordan KG, Gatto GJ, Wersinger SR, Hesse RA et al TC-5619: an alpha7 neuronal nicotinic receptor-selective agonist that demonstrates efficacy in animal models of the positive and negative symptoms and cognitive dysfunction of schizophrenia. Biochem Pharmacol. 2009; 78: 803– 812. 10.1016/j.bcp.2009.05.030 19482012 PMC3005247 · DOI
  23. [24]Prickaets J, van Goethem NP, Chesworth R, Shapiro G, Boess FG, Methfessel C et al EVP-6124, a novel and selective α7 nicotinic acetylcholine receptor partial agonist, improves memory performance by potentiating the acetylcholine response of α7 nicotinic acetylcholine receptors. Neuropharmacology 2012; 62: 1099– 1110. 10.1016/j.neuropharm.2011.10.024 22085888 · DOI
  24. [25]Turetsky BI, Calkins ME, Light GA, Olincy A, Radant AD and Swerdlow NR. Neurophysiological endophenotypes of schizophrenia: the viability of selected candidate measures. Schizophrenia Bulletin 2007; 33: 69– 94. 17135482 PMC2632291
  25. [26]Leonard S and Freedman R. Genetics of chromosome 15q13-q14 in schizophrenia. Biol Psychiatry 2006; 60: 115– 122. 16843094
  26. [27]Feuerbach D, Lingenhoel K, Olpe H-R, Vassout A, Gentsch C, Chaperon F et al The selective nicotinic acetylcholine receptor α7 agonist JN403 is active in animal models of cognition, sensory gating, epilepsy and pain. Neuropharmacology 2009; 56: 254– 263. 18793655
  27. [28]Hashimoto K, Iyo M, Freedman R and Stevens KE. Tropisetron improves deficient inhibitory auditory processing in DBA/2 mice: role of α7 nicotinic acetylcholine receptors. Psychopharmacology 2005; 183: 13– 19. 16136299
  28. [29]Shiina A, Shirayama Y, Niitsu T, Hashimoto T, Yoshida T, Hasegawa T et al A randomized, double-blind, placebo controlled trial of tropisetron in patients with schizophrenia. Ann Gen Psychiatry 2010; 9: 27– 36. 10.1186/1744-859X-9-27 20573264 PMC2901366 · DOI
  29. [30]Olincy A, Harris JG, Johnson LL, Pender V, Kongs S, Allensworth D et al Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Arch Gen Psychiatry 2006; 63: 630– 638. 16754836
  30. [31]Preskorn SH, Gawryl M, Dgetluck N, Palfreyman M, Bauer LO and Hilt DC. Normalizing effects of EVP-6124, an α7 nicotinic partial agonist, on event-related potentials and cognition: a proof of concept, randomized trial in patients with schizophrenia. J Psychiatr Pract. 2014; 20: 12– 24. 10.1097/01.pra.0000442935.15833.c5 24419307 · DOI
  31. [32]Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principal of protein-dye binding. Anal Biochem. 1976; 72: 248– 254. 942051
  32. [33]Anderson DJ, Bunnelle W, Surber B, Du J, Surowy C, Tribollet E et al [3H]A-585539 [(1S,4S)-2,2-dimethyl-5-(6-phenylpyridazin-3-yl)-5-aza-2-azoniabicyclo[2.2.1]heptane], a novel high-affinity alpha7 neuronal nicotinic receptor agonist: radioligand binding characterization to rat and human brain. J Pharmacol Exp Ther. 2008; 324: 179– 187. 17959745
  33. [34]Hope AG, Peters JA, Brown AM, Lambert JJ and Blackburn TP. Characterization of a human 5-hydroxytryptamine3 receptor type A (h5-HT3R-AS) subunit stably expressed in HEK 293 cells. Br J Pharmacol. 1996; 118: 1237– 1245. 8818349 PMC1909612
  34. [35]Birrell JM and Brown VJ. Medial frontal cortex mediates perceptual attentional set shifting in the rat. J Neurosci. 2000; 20: 2320– 2324. PMC6772641 10818167
  35. [36]Stefani MR, Groth K and Moghaddam B. Glutamate receptors in the rat medial prefrontal cortex regulates set shifting ability. Behav Neurosci. 2003; 117: 728– 737. 12931958
  36. [37]Broberg BV, Dias R, Glenthoj BY and Olsen CK. Evaluation of a neurodevelopmental model of schizophrenia—early postnatal PCP treatment in attentional set shifting. Behav Brain Res. 2008; 190: 160– 163 10.1016/j.bbr.2008.02.020 18367258 · DOI
  37. [38]Redrobe JP, Elster L, Federiksen K, Bundgaard C, de Jong IEM, Smith GP et al Negative modulation of GABAA α5 receptors by RO4938581 attenuates discrete sub-chronic and early postnatal phencyclidine (PCP)-induced cognitive deficits in rats. Psychopharmacology 2012; 221: 451– 468. 10.1007/s00213-011-2593-9 22124672 · DOI
  38. [39]Redrobe JP, Nielsen EO, Christensen JK, Peters D, Timmermann DB and Olsen GM. α7 nicotinic acetylcholine receptor activation ameliorates scopolamine-induced behavioral changes in a modified continuous Y-maze task in mice. Eur J Pharmacol. 2009; 602: 58– 65. 10.1016/j.ejphar.2008.09.035 18848931 · DOI
  39. [40]Sivarao DV, Chen P, Yang Y, Li YW, Pieschl R and Ahlijanian MK. NR2B antagonist CP-101,606 abolishes pitch-mediate deviance detection in awake rats. Front Psychiatry 2014; 5: article 96. PMC4122188 25140157
  40. [41]Briggs CA, Gronlien JH, Curzon P, Timmermann DB, Ween H, Thorin-Hagene K et al Role of channel activation in cognitive enhancement mediated by α7 nicotinic acetylcholine receptors. Br J Pharmacol. 2009; 158: 1486– 1494. 10.1111/j.1476-5381.2009.00426.x 19845675 PMC2795215 · DOI
  41. [42]Deardorff WJ, Shobassy A and Grossberg GT. Safety and clinical effects of EVP-6124 in subjects with Alzheimer’s Disease currently or previously receiving an acetylcholinesterase inhibitor medication. Expert Rev Neurother. 2015; 15: 7– 17. 10.1586/14737175.2015.995639 25495510 · DOI
  42. [43]Papke RL, Bagdas D, Kulkarni AR, Gould T, AlSharari SD, Thakur GA et al The analgesic-like properties of the alpha7 nAChR silent agonist NS6740 is associated with non-conducting conformations of the receptor. Neuropharmacology 2015; 91: 34– 42. 10.1016/j.neuropharm.2014.12.002 25497451 PMC4312719 · DOI
  43. [44]Nirogi R, Kandikere V, Komarneni P, Aleti R, Boggavarapu R, Bhyrapuneni G et al Quantification of methyllycaconitine, selective α7 nicotinic receptor agonist, in rodent plasma and brain tissue by liquid chromatography tandem mass spectrometry—application to neuropharmacokinetics of methyllycaconitine in rats. Biomed. Chromatogr. 2011; 25: 1273– 1282. 10.1002/bmc.1603 21337354 · DOI
  44. [45]Hashimoto K. Targeting of α7 nicotinic acetylcholine receptors in the treatment of schizophrenia and the use of auditory sensory gating as a translational biomarker. Curr Pharm Des. 2015; 21: 3797– 3806. 26044974 PMC5024727
  45. [46]Kaalund SS, Riise J, Broberg BV, Fabricius K, Karlsen AS, Secher T et al Differential expression of parvalbumin in neonatal phencyclidine-treated rats and socially isolated rats. J Neurochem. 2013; 124: 548– 557. 10.1111/jnc.12061 23083323 · DOI
  46. [47]Kjaerby C, Broberg BV, Kristiansen U and Dalby NO. Impaired GABAergic inhibition in the prefrontal cortex of early postnatal phencyclidine (PCP-treated rats. Cerebral Cortex 2014; 24: 2522– 2532. 10.1093/cercor/bht109 23613110 · DOI
  47. [48]O’Donnell CJ, Rogers BN, Bronk BS, Bryce DK, Coe JW, Cook KK et al Discovery of 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (CP-810,123), a novel α7 nicotinic acetylcholine receptor agonist for the treatment of cognitive disorders in schizophrenia: synthesis, SAR development, and in vivo efficacy in cognition models. J Med Chem. 2010; 53: 1222– 1237. 10.1021/jm9015075 20043678 · DOI
  48. [49]Wong DF, Kuwabara H, Pomper M, Holt DP, Brasic JR, George N et al Human brain imaging of α7 nAChR with [18F]ASEM: a new PET radiotracer for neuropsychiatry and determination of drug occupancy. Mol Imaging Biol. 2014; 16: 730– 738. 10.1007/s11307-014-0779-3 25145965 PMC5344036 · DOI

Authors
Bristow, L. J., Easton, A. E., Li, Y.-W., Sivarao, D. V., Lidge, R., Jones, K. M., Post-Munson, D., Daly, C., Lodge, N. J., Gallagher, L., Molski, T., Pieschl, R., Chen, P., Hendricson, A., Westphal, R., Cook, J., Iwuagwu, C., Morgan, D., Benitex, Y., King, D., Macor, J. E., Zaczek, R., & Olson, R.
Affiliations
Bristol-Myers Squibb (United States) (US)
Corresponding author
Bristow, Linda J.
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2016-07-28
Volume
11
Issue
7
Pages
e0159996
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0159996
PMC
PMC4965148
OpenAlex
W2485518701
Cited by
30
References
49
Citations by year
2026: 1 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 3 · 2020: 8 · 2019: 1 · 2018: 5 · 2017: 7 · 2016: 1
FWCI
2.77
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (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 › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
alpha7 nicotinic acetylcholine receptor, partial agonists, schizophrenia, cognitive impairment, sensory processing, auditory gating, novel object recognition memory, MK-801, PCP, set-shifting, receptor binding affinity, nootropic drugs, nicotinic agonists
MeSH terms
Animals, Cognition Disorders, Drug Evaluation, Preclinical, Humans, Male, Quinuclidines, Radioligand Assay, Schizophrenia, Spiro Compounds, Patch-Clamp Techniques, Mice, Rats, HEK293 Cells, alpha7 Nicotinic Acetylcholine Receptor

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review