In Vitro Pharmacological Characterization of a Novel Selective α7 Neuronal Nicotinic Acetylcholine Receptor Agonist ABT-107
Abstract
Enhancement of alpha7 nicotinic acetylcholine receptor (nAChR) activity is considered a therapeutic approach for ameliorating cognitive deficits present in Alzheimer's disease and schizophrenia. In this study, we describe the in vitro profile of a novel selective alpha7 nAChR agonist, 5-(6-[(3R)-1-azabicyclo[2,2,2]oct-3-yloxy]pyridazin-3-yl)-1H-indole (ABT-107). ABT-107 displayed high affinity binding to alpha7 nAChRs [rat or human cortex, [(3)H](1S,4S)-2,2-dimethyl-5-(6-phenylpyridazin-3-yl)-5-aza-2-azoniabicyclo[2.2.1]heptane (A-585539), K(i) = 0.2-0.6 nM or [(3)H]methyllycaconitine (MLA), 7 nM] that was at least 100-fold selective versus non-alpha7 nAChRs and other receptors. Functionally, ABT-107 did not evoke detectible currents in Xenopus oocytes expressing human or nonhuman alpha3beta4, chimeric (alpha6/alpha3)beta4, or 5-HT(3A) receptors, and weak or negligible Ca(2+) responses in human neuroblastoma IMR-32 cells (alpha3* function) and human alpha4beta2 and alpha4beta4 nAChRs expressed in human embryonic kidney 293 cells. ABT-107 potently evoked human and rat alpha7 nAChR current responses in oocytes (EC(50), 50-90 nM total charge, approximately 80% normalized to acetylcholine) that were enhanced by the positive allosteric modulator (PAM) 4-[5-(4-chloro-phenyl)-2-methyl-3-propionyl-pyrrol-1-yl]-benzenesulfonamide (A-867744). In rat hippocampus, ABT-107 alone evoked alpha7-like currents, which were inhibited by the alpha7 antagonist MLA. In dentate gyrus granule cells, ABT-107 enhanced spontaneous inhibitory postsynaptic current activity when coapplied with A-867744. In the presence of an alpha7 PAM [A-867744 or N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride (PNU-120596)], the addition of ABT-107 elicited MLA-sensitive alpha7 nAChR-mediated Ca(2+) signals in IMR-32 cells and rat cortical cultures and enhanced extracellular signal-regulated kinase phosphorylation in differentiated PC-12 cells. ABT-107 was also effective in protecting rat cortical cultures against glutamate-induced toxicity. In summary, ABT-107 is a selective high affinity alpha7 nAChR agonist suitable for characterizing the roles of this subtype in pharmacological studies.
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ABT-107 has low incidence of side effects at varying doses in patients.
“ABT-107 [5-(6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy] pyridazin-3-yl)-1H-indole; structure in Bitner et al., 2010] is a selective agonist with high affinity at a7 nAChRs that has been characterized as a cognitive enhancer in animal models of Alzheimer's disease and has low incidence of side effects at varying doses in patients (Bitner et al., 2010;Malysz et al., 2010;Othman et al., 2011).”
From Activation of α4β2*/α6β2* nicotinic receptors alleviates anxiety during nicotine withdrawal without upregulating nicotinic receptors (2014) · cites this paper as Malysz et al., 2010
ABT-107 is selective for the a7 subtype.
“ABT-107 is selective for the a7 subtype (Malysz et al., 2010) that has been implicated in generalized nicotine withdrawal syndrome (Nomikos et al., 1999).”
From Activation of α4β2*/α6β2* nicotinic receptors alleviates anxiety during nicotine withdrawal without upregulating nicotinic receptors (2014) · cites this paper as Malysz et al., 2010
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- Authors
- Malysz, J., Anderson, D. J., Grønlien, J. H., Ji, J., Bunnelle, W. H., Håkerud, M., Thorin-Hagene, K., Ween, H., Helfrich, R., Hu, M., Gubbins, E., Gopalakrishnan, S., Puttfarcken, P. S., Briggs, C. A., Li, J., Meyer, M. D., Dyhring, T., Ahring, P. K., Nielsen, E. Ø., Peters, D., Timmermann, D. B., & Gopalakrishnan, M.
- Affiliations
- Abbott (United States) (US)
- ORCID
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2010-09
- Volume
- 334
- Issue
- 3
- Pages
- 863-874
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2146089925
- Cited by
- 50
- References
- 40
- Citations by year
- 2025: 1 · 2023: 1 · 2021: 1 · 2020: 2 · 2019: 1 · 2018: 1 · 2017: 3 · 2016: 4 · 2015: 5 · 2014: 11 · 2013: 2 · 2012: 8
- FWCI
- 2.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (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, nicotinic agonists, receptor selectivity, methyllycaconitine, positive allosteric modulators, receptor desensitization, receptor resensitization, hippocampus, dentate gyrus granule cells
- MeSH terms
- Benzenesulfonamides, Animals, Calcium, Cell Line, Cells, Cultured, Cerebral Cortex, Electrophysiology, Humans, Indoles, Isoxazoles, Male, Oocytes, Phenylurea Compounds, Phosphorylation, Pyrroles, Quinuclidines, Radioligand Assay, Receptors, Nicotinic, Substrate Specificity, Sulfonamides, Xenopus, PC12 Cells, Rats, Sprague-Dawley, Patch-Clamp Techniques, Excitatory Amino Acid Antagonists, Nicotinic Agonists, Extracellular Signal-Regulated MAP Kinases, Rats, alpha7 Nicotinic Acetylcholine Receptor
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