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Novel 3-Pyridyl Ethers with Subnanomolar Affinity for Central Neuronal Nicotinic Acetylcholine Receptors
Abstract
Recent evidence indicating the therapeutic potential of cholinergic channel modulators for the treatment of central nervous system (CNS) disorders as well as the diversity of brain neuronal nicotine acetylcholine receptors (nAChRs) have suggested an opportunity to develop subtype-selective nAChR ligands for the treatment of specific CNS disorders with reduced side effect liabilities. We report a novel series of 3-pyridyl ether compounds which possess subnanomolar affinity for brain nAChRs and differentially activate subtypes of neuronal nAChRs. The synthesis and structure-activity relationships for the leading members of the series are described, including A-85380 (4a), which possesses ca.50 pM affinity for rat brain [(3)H]-(-)-cytisine binding sites and 163% efficacy compared to nicotine to stimulate ion flux at human alpha4beta2 nAChR subtype, and A-84543 (2a), which exhibits 84-fold selectivity to stimulate ion flux at human alpha4beta2 nAchR subtype compared to human ganglionic type nAChRs. Computational studies indicate that a reasonable superposition of a low energy conformer of 4A with (S)-nicotine and (-)-epibatidine can be achieved.
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Cited by
NEONICOTINOID INSECTICIDE TOXICOLOGY: Mechanisms of Selective Action
Tomizawa, M., & Casida, J. E. (2005) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.45.120403.095930 · Cited by 1,741
Neuronal nicotinic receptors in the human brain
Paterson, D., & Nordberg, A. (2000) · Progress in Neurobiology · doi:10.1016/s0301-0082(99)00045-3 · Cited by 782
Celie, P. H. N., van Rossum-Fikkert, S. E., van Dijk, W. J., Brejc, K., Smit, A. B., & Sixma, T. K. (2004) · Neuron · doi:10.1016/s0896-6273(04)00115-1 · Cited by 781
Neuronal Nicotinic Acetylcholine Receptors as Targets for Drug Discovery
Holladay, M. W., Dart, M. J., & Lynch, J. K. (1997) · Journal of Medicinal Chemistry · doi:10.1021/jm970377o · Cited by 444
Self-citation5-Iodo-A-85380, an α4β2 Subtype-Selective Ligand for Nicotinic Acetylcholine Receptors
Mukhin, A. G., Gündisch, D., Horti, A. G., Koren, A. O., Tamagnan, G., Kimes, A. S., Chambers, J., Vaupel, D. B., King, S. L., Picciotto, M. R., et al. (2000) · Molecular Pharmacology · doi:10.1124/mol.57.3.642 · Cited by 173
Musachio, J. L., Villemagne, V. L., Scheffel, U. A., Dannals, R. F., Dogan, A. S., Yokoi, F., & Wong, D. F. (1999) · Nuclear Medicine and Biology · doi:10.1016/s0969-8051(98)00101-2 · Cited by 67
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Self-citationChefer, S. I., Horti, A. G., Lee, K. S., Koren, A. O., Jones, D. W., Gorey, J. G., Links, J. M., Mukhin, A. G., Weinberger, D. R., & London, E. D. (1998) · Life Sciences · doi:10.1016/s0024-3205(98)00514-1 · Cited by 63
Kassiou, M., Eberl, S., Meikle, S. R., Birrell, A., Constable, C., Fulham, M. J., Wong, D. F., & Musachio, J. L. (2001) · Nuclear Medicine and Biology · doi:10.1016/s0969-8051(00)00206-7 · Cited by 58
Musachio, J. L., Scheffel, U., Finley, P. A., Zhan, Y., Mochizuki, T., Wagner, H. N., & Dannals, R. F. (1998) · Life Sciences · doi:10.1016/s0024-3205(98)00180-5 · Cited by 57
Horti, A. G., Koren, A. O., Lee, K. S., Mukhin, A. G., Vaupel, D. B., Kimes, A. S., Stratton, M., & London, E. D. (1999) · Nuclear Medicine and Biology · doi:10.1016/s0969-8051(98)00086-9 · Cited by 48
Imaging changes in synaptic acetylcholine availability in living human subjects
Esterlis, I., Hannestad, J. O., Bois, F., Sewell, R. A., Tyndale, R. F., Seibyl, J. P., Picciotto, M. R., Laruelle, M., Carson, R. E., & Cosgrove, K. P. (2013) · Journal of Nuclear Medicine · doi:10.2967/jnumed.112.111922 · Cited by 38
Kozikowski, A. P., Eaton, J. B., Bajjuri, K. M., Chellappan, S. K., Chen, Y., Karadi, S., He, R., Caldarone, B., Manzano, M., Yuen, P., et al. (2009) · ChemMedChem · doi:10.1002/cmdc.200900079 · Cited by 36
Vaupel, D. B., Tella, S. R., Huso, D. L., Wagner, V. O., Mukhin, A. G., Chefer, S. I., Horti, A. G., London, E. D., Koren, A. O., & Kimes, A. S. (2005) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.104.073999 · Cited by 28
Fujita, M., Al‐Tikriti, M. S., Tamagnan, G., Zoghbi, S. S., Bozkurt, A., Baldwin, R. M., & Innis, R. B. (2003) · Synapse · doi:10.1002/syn.10194 · Cited by 24
Deuther‐Conrad, W., Wevers, A., Becker, G., Schildan, A., Patt, M., Sabri, O., Steinbach, J., & Brust, P. (2006) · Synapse · doi:10.1002/syn.20232 · Cited by 12
Metadata
- Authors
- Abreo, M. A., Lin, N.-H., Garvey, D. S., Gunn, D. E., Hettinger, A.-M., Wasicak, J. T., Pavlik, P. A., Martin, Y. C., Donnelly-Roberts, D. L., Anderson, D. J., Sullivan, J. P., Williams, M., Arneric, S. P., & Holladay, M. W.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 1996-01-01
- Volume
- 39
- Issue
- 4
- Pages
- 817-825
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2953274112
- Cited by
- 231
- References
- 0
- FWCI
- 4.95
- Type
- journal article
- Language
- en
- Open access
- closed
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