Cited by 29Nicotinic Acetylcholine Receptors StudyNeuroscience and Neuropharmacology ResearchReceptor Mechanisms and Signaling

Concentration-response relationship of the α7 nicotinic acetylcholine receptor agonist FRM-17874 across multiple in vitro and in vivo assays

Stoiljkovic, Milan, Leventhal, Liza, Chen, Angela, Chen, Ting, Driscoll, Rachelle, Flood, Dorothy, Hodgdon, Hilliary, Hurst, Raymond +8 more·2015·Biochemical Pharmacology

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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Crossref · 10.1016/j.bcp.2015.07.006

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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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