POTENTIAL NICOTINIC RECEPTOR ANTAGONISTS: CHEMISTRY, RATIONALE, AND RESEARCH ROADMAP
Main Article Content
Keywords
Nicotinic acetylcholine receptor, receptor antagonists, subtype selectivity, medicinal chemistry, drug discovery, neurological disorders, pharmacology.
Abstract
Background: Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that regulate a wide array of physiological functions, such as cognition, pain, and autonomic functions. Their pathological activity has been associated with numerous disorders, including addiction, neurodegenerative diseases, and chronic pain. In spite of the nAChR's central role in physiological and pathological conditions, there are few effective and selective nAChR antagonists under development, primarily because of the variety of receptor subtypes and complex functional roles.
Objective: The objective of this study is to examine the current state of chemical agents acting as nicotinic receptor antagonists, to provide the scientific rationale for their development, and to establish a roadmap for moving forward in future research towards antagonists for clinical use.
Methods: A thorough review of literature was conducted that looked at chemical structure, binding characteristics, and functional effects of existing and potential new nicotinic receptor antagonists. Comparisons were then made of selective receptor subtype properties, pharmacological properties, and possible use as a treatment to illustrate trends and obstacles.
Results: Antagonistic activity at various nAChR subtypes is exhibited by diverse chemical classes including natural alkaloids, synthetic small molecules, or peptide-based components. Receptor modeling and high-throughput screening techniques have increased the number of selective antagonists; however, clinical translation is still hampered by low bioavailability, non-specific binding, and ever-changing subtype characterization.
Conclusions: The evolution of selective nicotinic receptor antagonists is still a promising but complex one, and it would be beneficial to incorporate structural and pharmacological research progress to inform a targeted research agenda that will focus on specificity, improved drug-like properties, and stronger preclinical assessment in an effort to expedite the innovation of therapeutics.
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4. Castillo, C., et al. (2013). Discovery of non peptide, small molecule antagonists of α9α10 nicotinic acetylcholine receptors as novel analgesics for the treatment of neuropathic and tonic inflammatory pain. Journal of Pharmacology and Experimental Therapeutics, 344(2), 301–310. https://doi.org/10.1124/jpet.112.201826 PMC
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6. Harvey, A. L. (2001). Twenty years of toxinology: interactions between toxins and nicotinic acetylcholine receptors. Toxicon, 39(1), 3 9.
7. Hu, J., et al. (2020). α Conotoxin GIC from Conus geographus is a novel peptide antagonist of neuronal α3β2 nicotinic receptors. Journal of Biological Chemistry, 295(21), 7301–7314. https://doi.org/10.1074/jbc.RA120.013756 JBC
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14. Shiembob, L. T., Papke, R. L., & McIntosh, J. M. (2024). Molecular basis for differential sensitivity of α conotoxin RegIIA at rat and human neuronal nicotinic acetylcholine receptors. Molecular Pharmacology. Advance online publication. https://doi.org/10.1124/molpharm.124.000121 American Chemical Society Publications
15. Vranken, W. F., et al. (2005). The peptide α conotoxin ImI blocks α7 nicotinic acetylcholine receptor function: structure, selectivity and binding interface. Biochemistry, 44(34), 11199 11207.
16. Wu, J., et al. (2017). Highly selective and potent α4β2 nAChR antagonist inhibits nicotine self administration and reinstatement in rats. Journal of Medicinal Chemistry, 60(24), 10092 10104. https://doi.org/10.1021/acs.jmedchem.7b01250 American Chemical Society Publications
17. Yang, L., Tae, H. S., Fan, Z., Shao, X., Xu, S., Zhao, S., Adams, D. J., & Wang, C. (2017). A novel lid covering peptide inhibitor of nicotinic acetylcholine receptors derived from αD Conotoxin GeXXA. Marine Drugs, 15(6), 164. (for GeXXA peptide)
18. Zamora Bustos, R., et al. (2015). Structure and function of a conotoxins: Selectivity toward nAChR subtypes and functional impacts. Peptides, 71, 60 68.
19. Zouridakis, M., et al. (2021). Selective antagonism of human α9α10 nicotinic acetylcholine receptors by novel peptidomimetics. British Journal of Pharmacology, 178(20), 4021–4036. (this is a newer peptidomimetic antagonists article)
20. Gotti, C., Zoli, M., & Clementi, F. (2006). Brain nicotinic acetylcholine receptors: Native subtypes and their relevance. Trends in Pharmacological Sciences, 27(9), 482 491.
21. Kasheverov, I. E., Kudryavtsev, D. Y., Shelukhina, I. V., Nikolaev, G. I., Utkin, Y. N., & Tsetlin, V. I. (2022). Marine origin ligands of nicotinic receptors: Low molecular compounds, peptides and proteins for fundamental research and practical applications. Biomolecules, 12(2), 189.
22. Manetti, D., Dei, S., Arias, H. R., Braconi, L., Gabellini, A., & Romanelli, M. N. (2023). Recent advances in the discovery of nicotinic acetylcholine receptor allosteric modulators. Molecules, 28(3), 1270. MDPI
23. Papke, R. L. (2014). Therapeutic targeting of α7 nicotinic acetylcholine receptors. Advances in Pharmacology, 70, 185 218.
24. Vincler, M., & McIntosh, J. M. (2007). Targeting the α9α10 nicotinic acetylcholine receptor to treat severe pain. Expert Opinion on Therapeutic Targets, 11(5), 643 653.
25. Hone, A. J., Servent, D., & McIntosh, J. M. (2015). α Conotoxins as tools for understanding the pharmacology of nicotinic acetylcholine receptors. European Journal of Pharmacology, 746, 124 140.
26. Tsetlin, V. I. (2015). Snake‐venom α neurotoxins and other binding proteins for nicotinic acetylcholine receptors. Acta Naturae, 7(1), 19 37.
27. Albuquerque, E. X., Pereira, E. F., Alkondon, M., & Rogers, S. W. (2009). Mammalian nicotinic acetylcholine receptors: From structure to function. Physiological Reviews, 89(1), 73 120.
28. Wang, L., Wu, X., Zhu, X., Zhangsun, D., Wu, Y., & Luo, S. (2022). A novel α4/7 conotoxin QuIA selectively inhibits α3β2 and α6/α3β4 nicotinic acetylcholine receptor subtypes with high efficacy. Marine Drugs, 20(2), 146. https://doi.org/10.3390/md20020146 MDPI
29. Ma, Y., Cao, Q., Yang, M., Gao, Y., Fu, S., Du, W., Adams, D. J., Jiang, T., Tae, H.-S., & Yu, R. (2022). Single Disulfide Conopeptide Czon1107, an allosteric antagonist of the human α3β4 nicotinic acetylcholine receptor. Marine Drugs, 20(8), 497. https://doi.org/10.3390/md20080497 PMC
30. Collins, R. L., Shearin, A. B., Williams, R. C., & Lane, S. (2018). The α3β4 nicotinic acetylcholine receptor antagonist 18 Methoxycoronaridine decreases binge like ethanol consumption in adult C57BL/6J mice. Behavioural Brain Research, 349, 65 72. https://doi.org/10.1016/j.bbr.2018.04.043 PubMed
31. Straub, C. J., Rusali, L. E., Kremiller, K. M., & Riley, A. P. (2023). What we have gained from ibogaine: α3β4 nicotinic acetylcholine receptor inhibitors as treatments for substance use disorders. Journal of Medicinal Chemistry, 66(1), 107 121. https://doi.org/10.1021/acs.jmedchem.2c01562 PubMed
32. He, Q., Dominguez, C. M., Schulteis, G., Luedtke, R. R., & Harris, A. C. (2023). Synthesis of α3β4 nicotinic acetylcholine receptor modulators derived from aristoquinoline that reduce reinstatement of cocaine seeking behavior. Journal of Pharmacology and Experimental Therapeutics, 387(2), 292 303. https://doi.org/10.1124/jpet.122.001451 PubMed
33. Toll, L., Brissette, W. H., Seidenberg, B., Paylor, R., & McIntosh, J. M. (2012). AT 1001, an α3β4 nicotinic acetylcholine receptor antagonist: selective, high affinity, and reduces nicotine self administration. Neuropsychopharmacology, 37(6), 1367 1376. https://doi.org/10.1038/npp.2011.293 probechem.com+1
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Sep 29, 2025
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Vyas Mitali Virendrabhai, Dr. Nishkruti R. Mehta, Khinya Ram, & Dr. Pragnesh Patani. (2025). POTENTIAL NICOTINIC RECEPTOR ANTAGONISTS: CHEMISTRY, RATIONALE, AND RESEARCH ROADMAP. Journal of Population Therapeutics and Clinical Pharmacology, 32(8), 1120-1137. https://doi.org/10.53555/1k4d4689
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Author Biographies
Vyas Mitali Virendrabhai
Student, Khyati College of Pharmacy, Palodiya, Ahmedabad
Dr. Nishkruti R. Mehta
Professor & Head, Department of Pharmacology, Khyati College of Pharmacy, Palodiya, Ahmedabad
Khinya Ram
Assitant Professor, Department of Pharmacology, Khyati College of Pharmacy, Palodiya, Ahmedabad
Dr. Pragnesh Patani
Principal, Khyati College of Pharmacy, Palodiya, Ahmedabad
How to Cite
Vyas Mitali Virendrabhai, Dr. Nishkruti R. Mehta, Khinya Ram, & Dr. Pragnesh Patani. (2025). POTENTIAL NICOTINIC RECEPTOR ANTAGONISTS: CHEMISTRY, RATIONALE, AND RESEARCH ROADMAP. Journal of Population Therapeutics and Clinical Pharmacology, 32(8), 1120-1137. https://doi.org/10.53555/1k4d4689