Structure−Activity Studies on 2-Methyl-3-(2(S)-pyrrolidinylmethoxy)pyridine (ABT-089): An Orally Bioavailable 3-Pyridyl Ether Nicotinic Acetylcholine Receptor Ligand with Cognition-Enhancing Properties
Abstract
2-Methyl-3-(2(S)-pyrrolidinylmethoxy)pyridine, ABT-089 (S-4), a member of the 3-pyridyl ether class of nicotinic acetylcholine receptor (nAChR) ligands, shows positive effects in rodent and primate models of cognitive enhancement and a rodent model of anxiolytic activity and possesses a reduced propensity to activate peripheral ganglionic type receptors. The profiles of S-4, its N-methyl analogue, and the corresponding enantiomers across several measures of cholinergic channel function in vitro and in vivo are presented, together with in vitro metabolism and in vivo bioavailability data. On the basis of its biological activities and favorable oral bioavailability, S-4 is an attractive candidate for further evaluation as a treatment for cognitive disorders.
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ABT-089 has been used successfully in patients with Alzheimer's disease and attention deficit disorder, with few unintended side effects.
“ABT-089 has been rigorously studied as a treatment of cognitive disorders and has been used successfully in patients with Alzheimer's disease and attention deficit disorder, with few unintended side effects (Lin et al., 1997;Rueter et al., 2004).”
From Activation of α4β2*/α6β2* nicotinic receptors alleviates anxiety during nicotine withdrawal without upregulating nicotinic receptors (2014) · cites this paper as Lin et al., 1997
A previous study showed ABT-089 decreased anxiety after short-term rather than long-term administration.
“Although a previous study showed ABT-089 decreased anxiety, this was after short-term rather than long-term administration (Lin et al., 1997).”
From Activation of α4β2*/α6β2* nicotinic receptors alleviates anxiety during nicotine withdrawal without upregulating nicotinic receptors (2014) · cites this paper as Lin et al., 1997
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Decker, M. W., Bannon, A. W., Curzon, P., Gunther, K. L., Brioni, J. D., Holladay, M. W., Lin, N.-H., Li, Y., Daanen, J. F., Buccafusco, J. J., et al. (1997) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)37015-6 · Cited by 88 · see citing works
Self-citationRueter, L. E., Anderson, D. J., Briggs, C. A., Donnelly‐Roberts, D. L., Gintant, G. A., Gopalakrishnan, M., Lin, N., Osinski, M. A., Reinhart, G. A., Buckley, M. J., et al. (2004) · CNS Drug Reviews · doi:10.1111/j.1527-3458.2004.tb00011.x · Cited by 70 · see citing works
Self-citationYohn, 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
- Authors
- Lin, N.-H., Gunn, D. E., Ryther, K. B., Garvey, D. S., Donnelly-Roberts, D. L., Decker, M. W., Brioni, J. D., Buckley, M. J., Rodrigues, A. D., Marsh, K. G., Anderson, D. J., Buccafusco, J. J., Prendergast, M. A., Sullivan, J. P., Williams, M., Arneric, S. P., & Holladay, M. W.
- Affiliations
- Abbott (United States) (US)
- Neuroscience Research, D-47W, Biotransformation, D-46V, and Drug Analysis, D-46W, Pharmaceutical Products Division, Abbott Laboratories, AP-10, 100 Abbott Park Road, Abbott Park, Illinois 60064-3500
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 1997-01-01
- Volume
- 40
- Issue
- 3
- Pages
- 385-390
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2950041389
- Cited by
- 67
- References
- 10
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 3 · 2020: 1 · 2017: 3 · 2016: 1 · 2015: 1 · 2014: 4 · 2012: 2
- FWCI
- 2.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- S^4, nicotinic acetylcholine receptors, cognitive enhancement, anxiolytic effects, structure-activity relationship, enantiomers, oral bioavailability, drug metabolism, cognitive disorders
- MeSH terms
- Quinolizidine Alkaloids, Administration, Oral, Alkaloids, Animals, Haplorhini, Azocines, Biological Availability, Bungarotoxins, Cell Line, Cognition, Dogs, Humans, Hypothermia, Isoxazoles, Ligands, Psychomotor Performance, Pyrrolidines, Quinolizines, Receptors, Nicotinic, Rubidium, Structure-Activity Relationship, Anti-Anxiety Agents, Molecular Structure, Maze Learning, Mice
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