In Vivo Pharmacological Characterization of a Novel Selective α7 Neuronal Nicotinic Acetylcholine Receptor Agonist ABT-107: Preclinical Considerations in Alzheimer's Disease
Abstract
We previously reported that alpha7 nicotinic acetylcholine receptor (nAChR) agonism produces efficacy in preclinical cognition models correlating with activation of cognitive and neuroprotective signaling pathways associated with Alzheimer's disease (AD) pathology. In the present studies, the selective and potent alpha7 nAChR agonist 5-(6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy] pyridazin-3-yl)-1H-indole (ABT-107) was evaluated in behavioral assays representing distinct cognitive domains. Studies were also conducted to address potential issues that may be associated with the clinical development of an alpha7 nAChR agonist. Specifically, ABT-107 improved cognition in monkey delayed matching to sample, rat social recognition, and mouse two-trial inhibitory avoidance, and continued to improve cognitive performance at injection times when exposure levels continued to decline. Rats concurrently infused with ABT-107 and donepezil at steady-state levels consistent with clinical exposure showed improved short-term recognition memory. Compared with nicotine, ABT-107 did not produce behavioral sensitization in rats or exhibit psychomotor stimulant activity in mice. Repeated (3 days) daily dosing of ABT-107 increased extracellular cortical acetylcholine in rats, whereas acute administration increased cortical extracellular signal-regulated kinase and cAMP response element-binding protein phosphorylation in mice, neurochemical and biochemical events germane to cognitive function. ABT-107 increased cortical phosphorylation of the inhibitory residue (Ser9) of glycogen synthase kinase-3, a primary tau kinase associated with AD pathology. In addition, continuous infusion of ABT-107 in tau/amyloid precursor protein transgenic AD mice reduced spinal tau hyperphosphorylation. These findings show that targeting alpha7 nAChRs may have potential utility for symptomatic alleviation and slowing of disease progression in the treatment AD, and expand the understanding of the potential therapeutic viability associated with the alpha7 nAChR approach in the treatment of AD.
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Both ABT-089 and ABT-107 enhance learning in naive animals.
“Both ABT-089 and ABT-107 enhance learning in naive animals (Decker et al., 1997;Bitner et al., 2010).”
From Activation of α4β2*/α6β2* nicotinic receptors alleviates anxiety during nicotine withdrawal without upregulating nicotinic receptors (2014) · cites this paper as Bitner et al., 2010
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 Bitner et al., 2010
Cites
Alzheimer's Disease: A Disorder of Cortical Cholinergic Innervation
Coyle, J. T., Price, D. L., & DeLong, M. R. (1983) · Science · doi:10.1126/science.6338589 · Cited by 3,050 · see citing works
Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP
Lewis, J., Dickson, D. W., Lin, W.-L., Chisholm, L., Corral, A., Jones, G., Yen, S.-H., Sahara, N., Skipper, L., Yager, D., et al. (2001) · Science · doi:10.1126/science.1058189 · Cited by 1,611 · see citing works
Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates
Dalley, J. W., Cardinal, R. N., & Robbins, T. W. (2004) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2004.09.006 · Cited by 1,329 · see citing works
Picciotto, M. R., Zoli, M., Rimondini, R., Léna, C., Marubio, L. M., Pich, E. M., Fuxe, K., & Changeux, J.-P. (1998) · Nature · doi:10.1038/34413 · Cited by 1,320 · see citing works
Pharmacology of nicotine: addiction, smoking-induced disease, and therapeutics
Benowitz, N. L. (2009) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.48.113006.094742 · Cited by 979 · see citing works
Bartus, R. T. (2000) · Experimental Neurology · doi:10.1006/exnr.2000.7397 · Cited by 829 · see citing works
Molecular Psychology: Roles for the ERK MAP Kinase Cascade in Memory
Adams, J. P., & Sweatt, J. D. (2002) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.42.082701.145401 · Cited by 588 · see citing works
Brain-derived neurotrophic factor is reduced in Alzheimer's disease
Connor, B., Young, D., Yan, Q., Faull, R. L. M., Synek, B., & Dragunow, M. (1997) · Molecular Brain Research · doi:10.1016/s0169-328x(97)00125-3 · Cited by 581 · see citing works
The effects of nicotine on locomotor activity in non‐tolerant and tolerant rats
Clarke, P. B. S., & Kumar, R. (1983) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.1983.tb09398.x · Cited by 457 · see citing works
Gong, B., Vitolo, O. V., Trinchese, F., Liu, S., Shelanski, M., & Arancio, O. (2004) · Journal of Clinical Investigation · doi:10.1172/jci22831 · Cited by 442 · see citing works
Alzheimer's Disease and Mild Cognitive Impairment
Kelley, B. J., & Petersen, R. C. (2007) · Neurologic Clinics · doi:10.1016/j.ncl.2007.03.008 · Cited by 328 · see citing works
Signaling by insulin-like growth factor 1 in brain
Bondy, C. A., & Cheng, C. M. (2004) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2004.02.042 · Cited by 323 · see citing works
Buckingham, S. D., Jones, A. K., Brown, L. A., & Sattelle, D. B. (2009) · Pharmacological Reviews · doi:10.1124/pr.108.000562 · Cited by 307 · see citing works
Yamamoto-Sasaki, M., Ozawa, H., Saito, T., Rösler, M., & Riederer, P. (1999) · Brain Research · doi:10.1016/s0006-8993(99)01220-2 · Cited by 198 · see citing works
Nicotinic α7 receptors: Synaptic options and downstream signaling in neurons
Berg, D. K., & Conroy, W. G. (2002) · Journal of Neurobiology · doi:10.1002/neu.10116 · Cited by 198 · see citing works
Bitner, 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
Self-citationActivating Akt and the brain's resources to drive cellular survival and prevent inflammatory injury.
Chong, Z. Z., Li, F., & Maiese, K. (2005) · PubMed · doi:10.14670/hh-20.299 · Cited by 181 · see citing works
Shaw, S., Bencherif, M., & Marrero, M. B. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204610200 · Cited by 172 · see citing works
Pharmacokinetic and pharmacodynamic profile of donepezil HCl following multiple oral doses
Rogers, Cooper, Sukovaty, Pederson, Lee, & Friedhoff (1998) · British Journal of Clinical Pharmacology · doi:10.1046/j.1365-2125.1998.0460s1007.x · Cited by 171 · see citing works
Leiser, S. C., Bowlby, M. R., Comery, T. A., & Dunlop, J. (2009) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2009.03.009 · Cited by 166 · see citing works
Nicotinic receptor agonists as neuroprotective/neurotrophic drugs. Progress in molecular mechanisms
Mudò, G., Belluardo, N., & Fuxé, K. (2006) · Journal of Neural Transmission · doi:10.1007/s00702-006-0561-z · Cited by 156 · see citing works
The Role of the Extracellular Signal-regulated Kinase Pathway in Memory Encoding
Giovannini, M. G. (2006) · Reviews in the Neurosciences · doi:10.1515/revneuro.2006.17.6.619 · Cited by 154 · see citing works
Seltzer, B. (2005) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.1.3.527 · Cited by 134 · see citing works
Levin, E. D., Petro, A. E., Rezvani, A. H., Pollard, N., Christopher, N. C., Strauss, M., Avery, J., Nicholson, J. L., & Rose, J. E. (2008) · Behavioural Brain Research · doi:10.1016/j.bbr.2008.08.048 · Cited by 123 · see citing works
Dissociations between the locomotor stimulant and depressant effects of nicotinic agonists in rats
Stolerman, I. P., Garcha, H. S., & Mirza, N. R. (1995) · Psychopharmacology · doi:10.1007/bf02246215 · Cited by 113 · see citing works
Working Memory and Learning in Early Alzheimer?s Disease
Germano, C., & Kinsella, G. (2005) · Neuropsychology Review · doi:10.1007/s11065-005-3583-7 · Cited by 108 · see citing works
One Hundred Years after the Discovery of Alzheimer's Disease. A Turning Point for Therapy?
Giacobini, E., & Becker, R. E. (2007) · Journal of Alzheimer s Disease · doi:10.3233/jad-2007-12105 · Cited by 92 · see citing works
Persistence of chronic nicotine-induced cognitive facilitation
Levin, E. D., Briggs, S. J., Christopher, N. C., & Rose, J. E. (1992) · Behavioral and Neural Biology · doi:10.1016/0163-1047(92)90399-o · Cited by 82 · see citing works
Bitner, R. S., Nikkel, A. L., Markosyan, S., Otte, S. L., Puttfarcken, P. S., & Gopalakrishnan, M. (2009) · Brain Research · doi:10.1016/j.brainres.2009.01.069 · Cited by 71 · see citing works
Self-citationRole of GSK‐3β activation and α7 nAChRs in Aβ1–42‐induced tau phosphorylation in PC12 cells
Hu, M., Waring, J. F., Gopalakrishnan, M., & Li, J. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05483.x · Cited by 67 · see citing works
Self-citationMolecular and Biochemical Features in Alzheimers Disease
Pallàs, M., & Camins, A. (2006) · Current Pharmaceutical Design · doi:10.2174/138161206778792967 · Cited by 63 · see citing works
Ring, R. H., Alder, J., Fennell, M., Kouranova, E. V., Black, I. B., & Thakker‐Varia, S. (2006) · Journal of Neurobiology · doi:10.1002/neu.20223 · Cited by 58 · see citing works
Marrero, M. B., Papke, R. L., Bhatti, B. S., Shaw, S., & Bencherif, M. (2004) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.103.061655 · Cited by 56 · see citing works
Anderson, D. J., Bunnelle, W. H., Surber, B. W., Du, J. Y., Surowy, C. S., Tribollet, E., Marguerat, A., Bertrand, D., & Gopalakrishnan, M. (2007) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.107.130062 · Cited by 52 · see citing works
Self-citationMalysz, J., Anderson, D. J., Grønlien, J. H., Ji, J., Bunnelle, W. H., Håkerud, M., Thorin-Hagene, K., Ween, H., Helfrich, R., Hu, M., et al. (2010) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.110.167072 · Cited by 50 · see citing works
Self-citationA computer-assisted cognitive test battery for aged monkeys
Buccafusco, J. J., Terry, A. V., & Murdoch, P. B. (2002) · Journal of Molecular Neuroscience · doi:10.1007/s12031-002-0030-6 · Cited by 29 · see citing works
Self-citationDonepezil-Induced Improvement in Delayed Matching Accuracy by Young and Old Rhesus Monkeys
Buccafusco, J. J., & Terry, A. V. (2004) · Journal of Molecular Neuroscience · doi:10.1385/jmn:24:1:085 · Cited by 24 · see citing works
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Bartzokis, G. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.01.015 · Cited by 142 · see citing works
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Wallace, T. L., & Bertrand, D. (2013) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.04.001 · Cited by 133 · see citing works
Young, J. W., Meves, J. M., & Geyer, M. A. (2013) · Behavioural Brain Research · doi:10.1016/j.bbr.2012.11.028 · Cited by 69 · see citing works
Malysz, J., Anderson, D. J., Grønlien, J. H., Ji, J., Bunnelle, W. H., Håkerud, M., Thorin-Hagene, K., Ween, H., Helfrich, R., Hu, M., et al. (2010) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.110.167072 · Cited by 50 · see citing works
Self-citationStoiljkovic, M., Leventhal, L., Chen, A., Chen, T., Driscoll, R., Flood, D., Hodgdon, H., Hurst, R., Nagy, D., Piser, T., et al. (2015) · Biochemical Pharmacology · doi:10.1016/j.bcp.2015.07.006 · Cited by 29 · see citing works
Yohn, N. L., Turner, J. R., & Blendy, J. A. (2014) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.113.211706 · Cited by 28 · see citing works
Othman, A. A., Lenz, R. A., Zhang, J., Li, J., Awni, W. M., & Dutta, S. (2011) · The Journal of Clinical Pharmacology · doi:10.1177/0091270010370460 · Cited by 24 · see citing works
- Authors
- 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., Anderson, D. J., Buccafusco, J., & Gopalakrishnan, M.
- Affiliations
- Abbott (United States) (US)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2010-09
- Volume
- 334
- Issue
- 3
- Pages
- 875-886
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2156683441
- Cited by
- 97
- References
- 37
- Citations by year
- 2024: 2 · 2023: 2 · 2021: 1 · 2020: 5 · 2019: 2 · 2018: 7 · 2017: 2 · 2016: 8 · 2015: 12 · 2014: 14 · 2013: 9 · 2012: 13
- FWCI
- 5.60
- 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
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- α7 nicotinic acetylcholine receptor agonist, Alzheimer's disease, cognitive enhancement, recognition memory, behavioral sensitization, ERK1/2 phosphorylation, CREB phosphorylation, glycogen synthase kinase-3, tau hyperphosphorylation, donepezil, nicotine
- MeSH terms
- Donepezil, Acetylcholine, Alzheimer Disease, Animals, Avoidance Learning, Behavior, Animal, Cognition, Electroencephalography, Indans, Indoles, Macaca mulatta, Male, Phosphorylation, Piperidines, Psychomotor Performance, Quinuclidines, Receptors, Nicotinic, Social Perception, Amyloid beta-Protein Precursor, tau Proteins, Rats, Sprague-Dawley, Cyclic AMP Response Element-Binding Protein, Mice, Knockout, Nootropic Agents, Nicotinic Agonists, Recognition, Psychology, Glycogen Synthase Kinase 3, Extracellular Signal-Regulated MAP Kinases, Mice, Rats, alpha7 Nicotinic Acetylcholine Receptor
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