Effects of Pyridine Ring Substitutions on Affinity, Efficacy, and Subtype Selectivity of Neuronal Nicotinic Receptor Agonist Epibatidine
Abstract
2'-Pyridine ring substituted analogs of epibatidine were assessed for equilibrium binding affinity, functional potency, and efficacy at rat neuronal nicotinic receptors expressed in Xenopus oocytes. Binding affinities were determined in membrane homogenates from oocytes expressing alpha2beta2, alpha2beta4, alpha3beta2, alpha3beta4, alpha4beta2, or alpha4beta4. Efficacy (relative to acetylcholine) and potency were measured electrophysiologically with oocytes expressing alpha3beta4, alpha4beta2, and alpha4beta4. Hydroxy, dimethylamino, and trifluoromethanesulfonate analogs had affinities too low for accurate measurement. The bromo analog had affinities 4- to 55-fold greater at beta2 than at beta4-containing receptors, modestly greater efficacy at alpha4beta4 than at alpha4beta2, and 5- to 10-fold greater potency at a4beta4 than at alpha3beta4 or alpha4beta2. The fluoro analog displayed affinities 52- to 875-fold greater at beta2- than at beta4-containing receptors, efficacy at alpha4beta4 receptors 3-fold greater than at alpha4beta2 and alpha3beta4, and was equipotent at all receptors tested. The norchloro analog showed affinities 114- to 3500-fold greater at beta2- than at beta4-containing receptors, 2-fold greater efficacy at alpha4beta2 and alpha4beta4 than at alpha3beta4, and 4- to 5-fold greater potency at alpha4beta4 and alpha3beta4 than at alpha4beta2. The amino analog displayed affinities 10- to 115-fold greater at beta2- than at beta4-containing receptors, 3-fold greater efficacy at alpha3beta4 than at alpha4beta2, and 2- to 4-fold greater potency at alpha3beta4 and alpha4beta4 than at alpha4beta2. Although these compounds displayed a variety of differences in affinity, efficacy, and potency, with one exception (binding affinity and functional potency at alpha4beta4 receptors) there were no significant correlations among these properties.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Epibatidine is a broad-spectrum nAChR ligand that binds with very high affinity (25-300 pM) to all known heteromeric nAChRs.
“Epibatidine is a broad-spectrum nAChR ligand that binds with very high affinity (25–300 pM) to all known heteromeric nAChRs (Avalos et al, 2002; Houghtling et al, 1995; Xiao and Kellar, 2004).”
From Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal (2013) · cites this paper as Avalos et al, 2002
Cites
Yung-Chi, C., & Prusoff, W. H. (1973) · Biochemical Pharmacology · doi:10.1016/0006-2952(73)90196-2 · Cited by 12,922 · see citing works
International Union of Pharmacology: Approaches to the Nomenclature of Voltage-Gated Ion Channels
Catterall, W. A., Chandy, K. G., Clapham, D. E., Gutman, G. A., Hofmann, F., Harmar, A. J., Abernethy, D. R., & Spedding, M. (2003) · Pharmacological Reviews · doi:10.1124/pr.55.4.5 · Cited by 7,126 · see citing works
Subunit stoichiometry of a mammalian K+ channel determined by construction of multimeric cDNAs
Liman, E. R., Tytgat, J., & Hess, P. (1992) · Neuron · doi:10.1016/0896-6273(92)90239-a · Cited by 1,072 · see citing works
Nicotinic Receptors at the Amino Acid Level
Corringer, P., Novère, N. G. L., & Changeux, J. (2000) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.40.1.431 · Cited by 823 · see citing works
Elgoyhen, A. B., Vetter, D. E., Katz, E., Rothlin, C. V., Heinemann, S. F., & Boulter, J. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.051622798 · Cited by 673 · see citing works
Lukas, R. J., Changeux, J., Novère, N. G. L., Albuquerque, E. X., Balfour, D. J. K., Berg, D. K., Bertrand, D., Chiappinelli, V. A., Clarke, P. B. S., Collins, A. C., et al. (1999) · Pharmacological Reviews · doi:10.1016/s0031-6997(24)01406-6 · Cited by 536 · see citing works
Epibatidine, a potent analgetic and nicotinic agonist.
Badio, B., & Daly, J. W. (1994) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)10139-9 · Cited by 389 · see citing works
Nicotinic receptors in the brain. Links between molecular biology and behavior
Picciotto, M. (2000) · Neuropsychopharmacology · doi:10.1016/s0893-133x(99)00146-3 · Cited by 354 · see citing works
Alkondon, M., Pereira, E. F. R., Barbosa, C. T. F., & Albuquerque, E. X. (1997) · PubMed · Cited by 326 · see citing works
Gerzanich, V., Peng, X.-D., Wang, F., Wells, G. B., Anand, R., Fletcher, S. R., & Lindstrom, J. M. (1995) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)10533-6 · Cited by 290 · see citing works
Xu, W., Orr‐Urtreger, A., Nigro, F., Gelber, S. E., Sutcliffe, C. B., Armstrong, D. L., Patrick, J. W., Role, L. W., Beaudet, A. L., & Biasi, M. D. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-21-09298.1999 · Cited by 283 · see citing works
Novère, N. G. L., Grütter, T., & Changeux, J. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.042699699 · Cited by 261 · see citing works
Decker, M. W., Brioni, J. D., Bannon, A. W., & Arnerić, S. P. (1995) · Life Sciences · doi:10.1016/0024-3205(94)00488-e · Cited by 256 · see citing works
Limburg, K. E., & Moran, M. A. (1986) · Springer series on environmental management · doi:10.1007/978-1-4612-4874-3_6 · Cited by 224 · see citing works
Hellström‐Lindahl, E., Mousavi, M. T., Zhang, X., Ravid, R., & Nordberg, A. K. (1999) · Molecular Brain Research · doi:10.1016/s0169-328x(99)00030-3 · Cited by 215 · see citing works
Gopalakrishnan, M., Monteggia, L. M., Anderson, D. J., Molinari, E. J., Piattoni-Kaplan, M., Donnelly-Roberts, D., Arneric, S. P., & Sullivan, J. P. (1996) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)12264-7 · Cited by 178 · see citing works
Localization of nicotinic receptor subunit mRNAs in monkey brain by in situ hybridization
Quik, M., Polonskaya, Y., Gillespie, A. J., Jakowec, M. W., Lloyd, G. K., & Langston, J. W. (2000) · The Journal of Comparative Neurology · doi:10.1002/1096-9861(20000911)425:1 · Cited by 172 · see citing works
Epibatidine is a nicotinic analgesic
Qian, C., Li, T., Shen, T. Y., Libertine-Garahan, L., Eckman, J. B., Biftu, T., & Ip, S. H. (1993) · European Journal of Pharmacology · doi:10.1016/0014-2999(93)90043-h · Cited by 169 · see citing works
Sullivan, J. P., Decker, M. W., Brioni, J. D., Donnelly‐Roberts, D. L., Anderson, D. J., Bannon, A. W., Kang, C. H., Adams, P., Piattoni-Kaplan, M., & Buckley, M. J. (1994) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)23809-5 · Cited by 168 · see citing works
Parker, M. J., Beck, A., & Luetje, C. W. (1998) · PubMed · Cited by 165 · see citing works
Self-citationNeuronal Nicotinic Receptor β2 and β4 Subunits Confer Large Differences in Agonist Binding Affinity
Parker, M. J., Beck, A., & Luetje, C. W. (1998) · Molecular Pharmacology · doi:10.1124/mol.54.6.1132 · Cited by 161 · see citing works
Self-citationDeterminants of Competitive Antagonist Sensitivity on Neuronal Nicotinic Receptor β Subunits
Harvey, S. C., & Luetje, C. W. (1996) · Journal of Neuroscience · doi:10.1523/jneurosci.16-12-03798.1996 · Cited by 153 · see citing works
Self-citationThe Pharmacology of (-)-Nicotine and Novel Cholinergic Channel Modulators
Brioni, J. D., Decker, M. W., Sullivan, J. P., & Arnerić, S. P. (1996) · Advances in pharmacology · doi:10.1016/s1054-3589(08)60950-3 · Cited by 134 · see citing works
Alkondon, M., Pereira, E. F. R., Barbosa, C. T. F., & Albuquerque, E. X. (1997) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)37139-3 · Cited by 127 · see citing works
Nicotinic receptors in the brain
Vidal, C. (1996) · Molecular and Chemical Neuropathology · doi:10.1007/bf02815199 · Cited by 118 · see citing works
Synthesis and nicotinic activity of epiboxidine: an isoxazole analogue of epibatidine
Badio, B., Garraffo, H. M., Plummer, C. V., et al. (1997) · European Journal of Pharmacology · doi:10.1016/s0014-2999(96)00939-9 · Cited by 95 · see citing works
Carroll, F. I., Liang, F., Navarro, H. A., et al. (2001) · Journal of Medicinal Chemistry · doi:10.1021/jm0100178 · Cited by 74 · see citing works
Self-citationMultiple spinal mediators in parenteral nicotine-induced antinociception.
Rogers, D. T., & Iwamoto, E. T. (1993) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)39353-5 · Cited by 70 · see citing works
Horti, A. G., Scheffel, U., Kimes, A. S., Musachio, J. L., Ravert, H. T., Mathews, W. B., Zhan, Y., Finley, P. A., London, E. D., & Dannals, R. F. (1998) · Journal of Medicinal Chemistry · doi:10.1021/jm980233p · Cited by 64 · see citing works
Characterization of the electrophysiological, biochemical and behavioral actions of epibatidine.
Bonhaus, D. W., Bley, K. R., Broka, C. A., et al. (1995) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)24546-3 · Cited by 58 · see citing works
The unusual nature of epibatidine responses at the α4β2 nicotinic acetylcholine receptor
Buisson, B., Vallejo, Y. F., Green, W. N., & Bertrand, D. (2000) · Neuropharmacology · doi:10.1016/s0028-3908(00)00158-1 · Cited by 45 · see citing works
Spang, J. E., Bertrand, S., Westera, G., et al. (2000) · Chemistry & Biology · doi:10.1016/s1074-5521(00)00138-1 · Cited by 39 · see citing works
Determinants of agonist binding affinity on neuronal nicotinic receptor beta subunits.
Parker, M. J., Harvey, S. C., & Luetje, C. W. (2001) · PubMed · Cited by 26 · see citing works
Self-citationDeterminants of Agonist Binding Affinity on Neuronal Nicotinic Receptor β Subunits
Parker, M. J., Harvey, S. C., & Luetje, C. W. (2001) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)29341-1 · Cited by 15 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Varenicline Is a Partial Agonist at α4β2 and a Full Agonist at α7 Neuronal Nicotinic Receptors
Mihalak, K. B., Carroll, F. I., & Luetje, C. W. (2006) · Molecular Pharmacology · doi:10.1124/mol.106.025130 · Cited by 558 · see citing works
Developmental effects of acute, chronic, and withdrawal from chronic nicotine on fear conditioning
Portugal, G. S., Wilkinson, D. S., Turner, J. R., Blendy, J. A., & Gould, T. J. (2012) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2012.04.003 · Cited by 79 · see citing works
Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal
Turner, J. R., Wilkinson, D. S., Poole, R. L., Gould, T. J., Carlson, G. C., & Blendy, J. A. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.105 · Cited by 29 · see citing works
- Authors
- Avalos, M., Parker, M. J., Maddox, F. N., Carroll, F. I., & Luetje, C. W.
- Affiliations
- University of Miami (US)
- RTI International (US)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2002-01
- Volume
- 302
- Issue
- 3
- Pages
- 1246-1252
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2141694713
- Cited by
- 36
- References
- 34
- Citations by year
- 2026: 2 · 2020: 1 · 2019: 1 · 2018: 1 · 2016: 1 · 2015: 1 · 2014: 4 · 2013: 3 · 2012: 2
- FWCI
- 1.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (T32 HL07188, T32HL007188)
- National Institute on Drug Abuse (R01DA012001, DA12001, DA08102, R01DA008102)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Alkaloids: synthesis and pharmacology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- epibatidine, neuronal nicotinic acetylcholine receptors, pyridine ring substitution, receptor subtype selectivity, binding affinity, alpha4beta2 receptor, nicotinic agonists, structure-activity relationship
- MeSH terms
- Animals, Binding, Competitive, Central Nervous System, Dose-Response Relationship, Drug, Electrophysiology, Neurons, Oocytes, Pyridines, Receptors, Nicotinic, Structure-Activity Relationship, Xenopus, Peripheral Nervous System, Patch-Clamp Techniques, Nicotinic Agonists, Bridged Bicyclo Compounds, Heterocyclic, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
