Concentration-response relationship of the α7 nicotinic acetylcholine receptor agonist FRM-17874 across multiple in vitro and in vivo assays
Abstract
Pharmacological activation of α7 nicotinic acetylcholine receptors (α7 nAChRs) may improve cognition in schizophrenia and Alzheimer's disease. The present studies describe an integrated pharmacological analysis of the effects of FRM-17874, an analogue of encenicline, on α7 nAChRs in vitro and in behavioral and neurophysiological assays relevant to cognitive function. FRM-17874 demonstrated high affinity binding to human α7 nAChRs, displacing [(3)H]-methyllacaconitine (Ki=4.3nM). In Xenopus laevis oocytes expressing human α7 nAChRs, FRM-17874 acted as an agonist, evoking inward currents with an EC50 of 0.42μM. Lower concentrations of FRM-17874 (0.01-3nM) elicited no detectable current, but primed receptors to respond to sub-maximal concentrations of acetylcholine. FRM-17874 improved novel object recognition in rats, and enhanced memory acquisition and reversal learning in the mouse water T-maze. Neurophysiological correlates of cognitive effects of drug treatment, such as synaptic transmission, long-term potentiation, and hippocampal theta oscillation were also evaluated. Modulation of synaptic transmission and plasticity was observed in rat hippocampal slices at concentrations of 3.2 and 5nM. FRM-17874 showed a dose-dependent facilitation of stimulation-induced hippocampal theta oscillation in mice and rats. The FRM-17874 unbound brain concentration-response relationship for increased theta oscillation power was similar in both species, exhibited a biphasic pattern peaking around 3nM, and overlapped with active doses and exposures observed in cognition assays. In summary, behavioral and neurophysiological assays indicate a bell-shaped effective concentration range and this report represents the first attempt to explain the concentration-response function of α7 nAChR-mediated pro-cognitive effects in terms of receptor pharmacology.
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Application of the nicotinic α7 ACh-R agonist FRM-17874 facilitated NOP in rats and dose-dependently enhanced theta oscillation induced by electrical stimulation in the rodent hippocampus.
“Application of the nicotinic α7 ACh-R agonist FRM-17874 facilitated NOP in rats and dose-dependently enhanced the theta oscillation induced by electrical stimulation in the rodent hippocampus”
From The medial prefrontal cortex - hippocampus circuit that integrates information of object, place and time to construct episodic memory in rodents: Behavioral, anatomical and neurochemical properties (2020) · cites this paper as Stoiljkovic et al., 2015
Cites
The rat brain in stereotaxic coordinates
Palkovits, M. (1983) · Neuropeptides · doi:10.1016/0143-4179(83)90049-5 · Cited by 28,959 · see citing works
The Rat Brain in Stereotaxic Coordinates
Paxinos, G., & Watson, C. (1983) · Elsevier eBooks · doi:10.1016/c2009-0-63235-9 · Cited by 28,585 · see citing works
The mouse brain in stereotaxic coordinates
Konsman, J. (2003) · Psychoneuroendocrinology · doi:10.1016/s0306-4530(03)00088-x · Cited by 16,796 · see citing works
Yung-Chi, C., & Prusoff, W. H. (1973) · Biochemical Pharmacology · doi:10.1016/0006-2952(73)90196-2 · Cited by 12,922 · see citing works
The Mouse Brain in Stereotaxic Coordinates
Paxinos, G. (2001) · Cited by 12,859 · see citing works
A new one-trial test for neurobiological studies of memory in rats. 1: behavioral data
Ennaceur, A., & Delacour, J. (1988) · Behavioural Brain Research · doi:10.1016/0166-4328(88)90157-x · Cited by 3,223 · see citing works
Memory, navigation and theta rhythm in the hippocampal-entorhinal system
Buzsáki, G., & Moser, E. I. (2013) · Nature Neuroscience · doi:10.1038/nn.3304 · Cited by 1,847 · see citing works
A network dysfunction perspective on neurodegenerative diseases
Palop, J. J., Chin, J., & Mucke, L. (2006) · Nature · doi:10.1038/nature05289 · Cited by 683 · see citing works
Proof-of-Concept Trial of an α7 Nicotinic Agonist in Schizophrenia
D, A. O. M., Harris, J. G., Johnson, L. L., Pender, V., Kongs, S., Allensworth, D., Ellis, J., Zerbe, G. O., Leonard, S. S., Stevens, K. E., et al. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.6.630 · Cited by 531 · see citing works
Neurophysiological biomarkers for drug development in schizophrenia
Javitt, D. C., Spencer, K., Thaker, G. K., Winterer, G., & Hajós, M. (2007) · Nature Reviews Drug Discovery · doi:10.1038/nrd2463 · Cited by 340 · see citing works
Self-citationInhibition-induced theta resonance in cortical circuits
Stark, E., Eichler, R., Roux, L., Fujisawa, S., Rotstein, H. G., & Buzsáki, G. (2013) · Neuron · doi:10.1016/j.neuron.2013.09.033 · Cited by 326 · see citing works
Theta rhythm and the encoding and retrieval of space and time
Hasselmo, M. E., & Stern, C. E. (2013) · NeuroImage · doi:10.1016/j.neuroimage.2013.06.022 · Cited by 261 · see citing works
KITAGAWA, H., TAKENOUCHI, T., Azuma, R., Wesnes, K. A., Kramer, W. G., Clody, D. E., & Burnett, A. L. (2002) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300028 · Cited by 238 · see citing works
Hajós, M., Hurst, R. S., Hoffmann, W. E., Krause, M., Wall, T. M., Higdon, N. R., & Groppi, V. E. (2005) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.104.076968 · Cited by 225 · see citing works
Self-citationTargeting the nicotinic alpha7 acetylcholine receptor to enhance cognition in disease
Wallace, T. L., & Porter, R. H. P. (2011) · Biochemical Pharmacology · doi:10.1016/j.bcp.2011.06.034 · Cited by 225 · see citing works
Prickaerts, J., van Goethem, N. V., Chesworth, R., Shapiro, G., Boess, F., Methfessel, C., Reneerkens, O., Flood, D., Hilt, D., Gawryl, M., et al. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.10.024 · Cited by 223 · see citing works
Self-citationDetection and trapping of intermediate states priming nicotinic receptor channel opening
Mukhtasimova, N., Lee, W. Y., Wang, H.-L., & Sine, S. M. (2009) · Nature · doi:10.1038/nature07923 · Cited by 219 · see citing works
Bodnar, A. L., Cortes-Burgos, L. A., Cook, K. K., Dinh, D. M., Groppi, V. E., Hajós, M., Higdon, N. R., Hoffmann, W. E., Hurst, R. S., Myers, J. K., et al. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm049363q · Cited by 216 · see citing works
Self-citationThomsen, M. S., Hansen, H. H., Timmerman, D. B., & Mikkelsen, J. (2010) · Current pharmaceutical design · doi:10.2174/138161210790170094 · Cited by 204 · see citing works
Nicotinic α7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex
Yang, Y., Paspalas, C. D., Jin, L. E., Picciotto, M. R., Arnsten, A. F. T., & Wang, M. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1307849110 · Cited by 188 · see citing works
McNaughton, N., Kocsis, B., & Hajós, M. (2007) · Behavioural Pharmacology · doi:10.1097/fbp.0b013e3282ee82e3 · Cited by 187 · see citing works
Self-citationBitner, R. S., Bunnelle, W. H., Anderson, D. J., Briggs, C. A., Buccafusco, J. J., Curzon, P., Decker, M. W., Frost, J. M., Grønlien, J. H., Gubbins, E. J., et al. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.2444-07.2007 · Cited by 184 · see citing works
Lieberman, J. A., Dunbar, G. C., Segreti, A. C., Girgis, R. R., Seoane, F., Beaver, J. S., Duan, N., & Hosford, D. A. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2012.259 · Cited by 176 · see citing works
α7-Nicotinic Acetylcholine Receptor Agonists for Cognitive Enhancement in Schizophrenia
Freedman, R. (2013) · Annual Review of Medicine · doi:10.1146/annurev-med-092112-142937 · Cited by 155 · see citing works
Preskorn, S., Gawryl, M., Dgetluck, N., Palfreyman, M., Bauer, L., & Hilt, D. (2014) · Journal of Psychiatric Practice · doi:10.1097/01.pra.0000442935.15833.c5 · Cited by 135 · see citing works
Network mechanisms of theta related neuronal activity in hippocampal CA1 pyramidal neurons
Losonczy, A., Zemelman, B. V., Vaziri, A., & Magee, J. C. (2010) · Nature Neuroscience · doi:10.1038/nn.2597 · Cited by 118 · see citing works
Rubio, S. E., Vega‐Flores, G., Martínez, A., Bosch, C., Pérez‐Mediavilla, A., Río, J. D., Gruart, A., Delgado‐García, J. M., Soriano, E., & Pascual, M. (2012) · The FASEB Journal · doi:10.1096/fj.12-208413 · Cited by 98 · see citing works
Walling, D. P., Marder, S. R., Kane, J. M., Fleischhacker, W. W., Keefe, R. S. E., Hosford, D. A., Dvergsten, C., Segreti, A. C., Beaver, J. S., Toler, S. M., et al. (2015) · Schizophrenia Bulletin · doi:10.1093/schbul/sbv072 · Cited by 98 · see citing works
Bitner, R. S., Bunnelle, W. H., Decker, M. W., Drescher, K. U., Kohlhaas, K. L., Markosyan, S., Marsh, K. C., Nikkel, A. L., Browman, K., Radek, R., et al. (2010) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.110.167213 · Cited by 97 · see citing works
Song, C., Murray, T. A., Kimura, R., Wakui, M., Ellsworth, K. R., Javedan, S. P., Marxer-Miller, S., Lukas, R. J., & Wu, J. (2005) · Neuropharmacology · doi:10.1016/j.neuropharm.2005.01.003 · Cited by 89 · see citing works
Age-dependent disruption in hippocampal theta oscillation in amyloid-β overproducing transgenic mice
Scott, L., Feng, J., Kiss, T., Needle, E., Atchison, K. P., Kawabe, T. T., Milici, A. J., Hajós‐Korcsok, É., Riddell, D. R., & Hajós, M. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2011.12.010 · Cited by 87 · see citing works
Self-citation?7-Nicotinic Receptors and Cognition
Levin, E. D. (2012) · Current Drug Targets · doi:10.2174/138945012800398937 · Cited by 82 · see citing works
Umbricht, D., Keefe, R. S. E., Murray, S., Lowe, D. A., Porter, R., Garibaldi, G. M., & Santarelli, L. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.17 · Cited by 80 · see citing works
Deardorff, W., Shobassy, A., & Grossberg, G. (2015) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.2015.995639 · Cited by 79 · see citing works
Recognition Memory Correlates of Hippocampal Theta Cells
Wiebe, S. P., & Staubli, U. V. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-11-03955.2001 · Cited by 74 · see citing works
Targeting α7 Nicotinic Acetylcholine Receptors in the Treatment of Schizophrenia
Hajós, M., & Rogers, B. N. (2010) · Current Pharmaceutical Design · doi:10.2174/138161210790361434 · Cited by 73 · see citing works
Self-citationAlpha7 neuronal nicotinic receptors as a drug target in schizophrenia
Wallace, T. L., & Bertrand, D. (2012) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2013.736498 · Cited by 72 · see citing works
Self-citationActivation of α7 acetylcholine receptors augments stimulation‐induced hippocampal theta oscillation
Siok, C. J., Rogers, J. A., Kocsis, B., & Hajós, M. (2006) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2005.04560.x · Cited by 68 · see citing works
Self-citationAn automated system for intracellular and intranuclear injection
Hogg, R. C., Bandelier, F., Benoit, A., et al. (2007) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2007.11.028 · Cited by 65 · see citing works
Kinney, G. G., Patiño, P., Mermet-Bouvier, Y., Starrett, J. E., & Gribkoff, V. K. (1999) · PubMed · Cited by 64 · see citing works
Water T-maze: A useful assay for determination of repetitive behaviors in mice
Guariglia, S. R., & Chadman, K. K. (2013) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2013.08.019 · Cited by 61 · see citing works
Modulation of alpha7 nicotinic receptor-mediated calcium influx by nicotinic agonists.
Quik, M., Philie, J., & Choremis, J. (1997) · PubMed · Cited by 59 · see citing works
Barbier, A. J., Hilhorst, M., Vliet, A. V., Snyder, P., Palfreyman, M. G., Gawryl, M., Dgetluck, N., Massaro, M., Tiessen, R., Timmerman, W., et al. (2015) · Clinical Therapeutics · doi:10.1016/j.clinthera.2014.09.013 · Cited by 51 · see citing works
Bürli, T., Baer, K., Ewers, H., Sidler, C., Fuhrer, C., & Fritschy, J. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011507 · Cited by 44 · see citing works
Li, S., Topchiy, I., & Kocsis, B. (2007) · Synapse · doi:10.1002/syn.20388 · Cited by 42 · see citing works
Gault, L. M., Ritchie, C. W., Robieson, W., Pritchett, Y., Othman, A. A., & Lenz, R. A. (2015) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1016/j.trci.2015.06.001 · Cited by 41 · see citing works
Kinney, G. G., Patiño, P., Mermet-Bouvier, Y., Starrett, J. E., & Gribkoff, V. K. (1999) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)35076-1 · Cited by 41 · see citing works
Kiss, T., Feng, J., Hoffmann, W. E., Shaffer, C. L., & Hajós, M. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.01.058 · Cited by 36 · see citing works
Self-citationOndrejčák, T., Wang, Q., Kew, J. N. C., Virley, D. J., Upton, N., Anwyl, R., & Rowan, M. J. (2011) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2011.12.008 · Cited by 35 · see citing works
Nicotine induction of theta frequency oscillations in rodent hippocampus in vitro
Lu, C., & Henderson, Z. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2009.11.072 · Cited by 34 · see citing works
Locchi, F., Dall’Olio, R., Gandolfi, O., et al. (2007) · Neuroscience Letters · doi:10.1016/j.neulet.2007.06.023 · Cited by 33 · see citing works
Kroker, K. S., Rast, G. F., & Rosenbrock, H. (2011) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2011.09.167 · Cited by 31 · see citing works
Modulation of α7 Nicotinic Receptor-Mediated Calcium Influx by Nicotinic Agonists
Quik, M., Philie, J., & Choremis, J. (1997) · Molecular Pharmacology · doi:10.1016/s0026-895x(24)13492-x · Cited by 31 · see citing works
Guadagna, S., Bundgaard, C., Hovelsø, N., et al. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.01.014 · Cited by 28 · see citing works
Russo, P., Bufalo, A. D., Frustaci, A., Fini, M., & Cesario, A. (2014) · Current Pharmaceutical Design · doi:10.2174/1381612820666140316130720 · Cited by 26 · see citing works
Ondansetron in the Treatment of Cognitive Decline in Alzheimer Dementia
Dysken, M. W., Kuskowski, M. A., & Love, S. B. (2002) · American Journal of Geriatric Psychiatry · doi:10.1097/00019442-200203000-00013 · Cited by 21 · see citing works
Ondansetron results in improved auditory gating in DBA/2 mice through a cholinergic mechanism
Wildeboer, K. M., Zheng, L., Choo, K. S., & Stevens, K. E. (2009) · Brain Research · doi:10.1016/j.brainres.2009.08.075 · Cited by 19 · see citing works
Wigestrand, M. B., Mineur, Y. S., Heath, C. J., Fonnum, F., Picciotto, M. R., & Walaas, S. I. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07415.x · Cited by 16 · see citing works
Tang, C., Chen, T., Kapadnis, S., Hodgdon, H., Tao, Y., Chen, X., Wen, M., Costa, D., Murphy, D., Nolan, S., et al. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2014.07.023 · Cited by 12 · see citing works
Self-citationImpaired Hippocampal Theta Oscillations in the Mice Null Alpha7 Nicotinic Acetylcholine Receptors
Jin, Y., Quan-xi, S., Shen, J., Marks, M. J., & Wu, J. (2013) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.12138 · Cited by 4 · see citing works
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- Authors
- Stoiljkovic, M., Leventhal, L., Chen, A., Chen, T., Driscoll, R., Flood, D., Hodgdon, H., Hurst, R., Nagy, D., Piser, T., Tang, C., Townsend, M., Tu, Z., Bertrand, D., Koenig, G., & Hajós, M.
- Affiliations
- FORUM Pharmaceuticals (United States) (US)
- HiQScreen (Switzerland) (CH)
- Corresponding author
- Leventhal, Liza
- Venue
- Biochemical Pharmacology
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 97
- Issue
- 4
- Pages
- 576-589
- ISSN
- 0006-2952 (ISSN-L)
- OpenAlex
- W2195315988
- Cited by
- 29
- References
- 60
- Citations by year
- 2025: 1 · 2021: 4 · 2020: 4 · 2019: 2 · 2018: 3 · 2017: 9 · 2016: 5 · 2015: 1
- FWCI
- 2.60
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- alpha7 nicotinic acetylcholine receptor, concentration-dependent effects, bell-shaped dose-response, receptor agonism, receptor priming, acetylcholine, novel object recognition, reversal learning, memory acquisition, hippocampal theta oscillations, synaptic transmission, long-term potentiation, cognitive enhancement, schizophrenia, Alzheimer's disease
- MeSH terms
- Animals, Behavior, Animal, Cricetulus, Dose-Response Relationship, Drug, Female, Gene Expression Regulation, Cricetinae, Hippocampus, Humans, Learning, Male, Memory, Mice, Inbred C57BL, Oocytes, Protein Binding, Quinuclidines, Thiophenes, Xenopus laevis, CHO Cells, Rats, Sprague-Dawley, Rats, Wistar, Mice, Rats, alpha7 Nicotinic Acetylcholine Receptor
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