Nicotine Analogs: Structure-Affinity Relationships For Central Nicotinic Acetylcholinergic Receptor Binding

  • Richard A. Glennon
  • Małgorzata Dukat


Cholinergic receptors are one of the oldest known populations of neurotransmitter receptors, and acetylcholine is their natural ligand. Shortly after the discovery of acetylcholinergic receptors it was realized that the actions of cholinergic agents could best be described by invoking two distinct populations of receptors: muscarinic acetylcholinergic receptors and nicotinic acetylcholinergic receptors (nAChRs). Investigations during the 1950s to the 1980s identified a number of interesting nAChR agonists and antagonists using, for the most part, isolated peripheral tissue or organ preparations. Indeed, nicotinic pharmacophores were identified and are still the subject of continuing investigations. Relatively less has been done with nAChRs at the level of the central nervous system. However, the last decade has witnessed a significant resurgence of interest in nAChRs, particularly in central nAChRs, for several reasons. Nicotinic receptors were identified in brain homogenates, and techniques and radioligands were developed for their investigation. Furthermore, there exists today a better understanding of the structure of nAChRs. These receptors are pentameric units that are directly associated with an ion channel. The receptors are composed of various a (α29), β (β1β4), y, and δ subunit combinations (see Shacka and Robinson 1996; Holladay et al. 1997) and their exact composition likely dictates their pharmacology and binding characteristics. There is also a difference between peripheral and central nAChRs, and the major population of brain nAChRs appears to be of the α4β2 type. Further fueling the interest in central nAChRs is evidence that such receptors may be involved in appetite, memory, analgesia, and various other physiological processes as well as in anxiety, memory, and certain mental and neurological disorders (Arneric and Brioni 1998). Although nicotine (1a), a naturally occurring nAChR ligand, is associated with a variety of toxic side effects, there is no reason to believe that these side effects are inextricably linked to the beneficial effects of nicotinic ligands. Thus, we and others have begun investigations to identify the structureactivity relationships (SAR) for nicotinic agonist and antagonist activity, and structure-affinity relationships (SAFIR) for central nAChR binding, to ultimately develop novel nicotinic agents with greater selectivity and reduced toxicity that may be useful for disorders involving nAChRs.


Neuronal Nicotinic Acetylcholine Receptor Potent Analgesic Activity Nicotinic Ligand Nicotinic Agent nAChR Ligand 
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  1. Abood LG, Lu X, Banerjee S (1987) Receptor binding characteristics of a 3H-labelled azetidine analogue of nicotine. Biochem Pharmacol 36:2337–2341PubMedCrossRefGoogle Scholar
  2. Abreo MA, Lin NH, Garvey DS, Gunn DE, Hettinger AM, Wasicak JT, Pavlik PA, Martin YC, Donnelly-Roberts DL, Anderson DJ, Sullivan JP, Williams M, Arneric SP, Holladay MW (1996) Novel 3-pyridyl ethers with subnanomolar affinity for central neuronal nicotinic acetylcholine receptors. J Med Chem 39:817–825PubMedCrossRefGoogle Scholar
  3. Arneric SP Brioni JD (1998) Neuronal nicotinic receptors: pharmacology and therapeutic opportunities. John Wiley and Sons, New YorkGoogle Scholar
  4. Barlow RB, Johnson O (1989) Relations between structure and nicotine-like activity: X-ray crystal structure analysis of (-)-cytisine and (-)-lobeline hydrochloride and a comparison with (-)-nicotine and other nicotine-like compounds. Br J Pharmacol 98:799–808PubMedCrossRefGoogle Scholar
  5. Beers WH, Reich E (1970) Structure and activity of acetylcholine. Nature (Lond) 225:917–922CrossRefGoogle Scholar
  6. Caldwell WS, Benchenif M, Bhatti BS, Deo NM, Dobson GP, Dull GM, Lipiello PM, Lovette ME, Miller CH, Ravard A, Schmitt JD, Crooks PA (1997) Synthesis and structure-activity relationships of analogs of RJR-2403, a CNS-selective nicotinic agonist. Abstracts of International Business Communications Symposium on Nicotinic Acetylcholine Receptors as Pharmaceutical Targets, Washington, DC, July 24-25Google Scholar
  7. Cheng YX, Fiedler W, Dukat M, Damaj I, Martin B, Glennon RA (1995) Conformationally-restricted aminomethylpyridine derivatives as novel nicotine receptor ligands. VA J Sci 46:135Google Scholar
  8. Dowd M, Dukat M, El-Zahaby M, Glennon RA (1997) Role of 6-position substituents on the binding of nicotine at nicotinic cholinergic receptors. VA J Sci 48:137Google Scholar
  9. Dukat M (1994) 208/210 a.k.a. epibatidine. Med Chem Res 4:433–439Google Scholar
  10. Dukat M, Herndon JL, Glennon RA (1995) Epibatidine: reconsideration of the nicotine receptor pharmacophore. NIDA Res Mono 162:286.Google Scholar
  11. Dukat M, Damaj MI, Glassco W, Dumas D, May EL, Martin BR, Glennon RA (1994) Epibatidine: a very high affinity nicotine receptor ligand. Med Chem Res 4:131–139Google Scholar
  12. Dukat M, Fiedler W, Dumas D, Damaj I, Martin BR, Rosecrans JA, James JR, Glennon RA (1996) Pyrrolidine-modified and 6-substituted analogs of nicotine: a structure-affinity investigation. Eur J Med Chem 31:875–888CrossRefGoogle Scholar
  13. Dukat M, Dowd M, Damaj MI, Martin BR, El-Zahabi M, Glennon RA (1998) Synthesis, receptor binding, and QSAR studies on 6-substituted nicotine derivatives as cholinergic ligands. Eur J Med Chem, in pressGoogle Scholar
  14. Garvey DS, Wasicak JT, Elliott RL, Lebold SA, Hettinger AM, Carrera GM, Lin NH, He Y, Holladay MW, Anderson DJ, Cadman ED, Raszkiewicz JL, Sullivan JP, Arneric SP (1994) Ligands for brain cholinergic channel receptors: synthesis and in vitro characterization of novel isoxazoles and isothiazoles as biosteric replacements for the pyridine ring of nicotine. J Med Chem 37: 4455–4463PubMedCrossRefGoogle Scholar
  15. Glassco W, May EL, Damaj MI, Martin BR (1993a) In vivo and in vitro activity of some N-substituted (±)-nornicotine analogs. Med Chem Res 4: 273–282Google Scholar
  16. Glassco W, Suchocki J, George C, Martin BR, May EL (1993b) Synthesis, optical resolution, absolute configuration, and preliminary pharmacology of (+)-and (-)-cis-2,3,3a,4,5,9b-hexahydro-1-methyl-lH-pyrrolo[3,2-h]isoquinoline,a structural analog of nicotine. J Med Chem 36: 3381–3385PubMedCrossRefGoogle Scholar
  17. Glennon RA, Dukat M (1996) Nicotine receptor ligands. Med Chem Res 6:465–486Google Scholar
  18. Glennon RA, Dukat M (1998) Nicotinic cholinergic receptor pharmacophores. In: Arneric SP, Brioni JD (Eds) Neuronal nicotinic receptors: pharmacology and therapeutic opportunities. John Wiley and Sons, New York, pp 271–284Google Scholar
  19. Glennon RA, Herndon JL, Dukat M (1994) Epibatidine-aided studies toward definition of a nicotinic receptor pharmacophore. Med Chem Res 4:461–473Google Scholar
  20. Glennon RA, Maarouf A, Fahmy S, Martin B, Fan F, Yousif Y, Shafik RM, Dukat M (1993) Structure-activity relationships of simple nicotine analogs. Med Chem Res 2:546–551Google Scholar
  21. Haglid F (1967) Studies on pyridine alkaloidsand their analogues. Acta Pharm Suec 4:117–138.PubMedGoogle Scholar
  22. Holladay MW, Dart MJ, Lynch JK (1997) Neuronal nicotinic acetylcholine receptors as targets for drug discovery. J Med Chem 40:4169–4194PubMedCrossRefGoogle Scholar
  23. Lin N-H, Carrera GM, Anderson DJ (1994) Synthesis and evaluation of nicotine analogs as neuronal nicotinic acetylcholine receptor ligands. J Med Chem 37:3542–3553PubMedCrossRefGoogle Scholar
  24. Shacka JJ, Robinson SE (1996) Central and peripheral anatomy of nicotine sites. Med Chem Res 6:444–464Google Scholar
  25. Sheridan RP, Nilakantan R, Dixon JS, Venkataraghavan R (1986) The ensemble approach to distance geometry: Application to the nicotinic pharmacophore. J Med Chem 29:899–906PubMedCrossRefGoogle Scholar
  26. Spande TF, Garraffo HM, Edwards MW, Yeh HJC, Pannell L, Daly JW (1992) Epibatidine: a novel (chloropyridyl)azabicycloheptane with potent analgesic activity from an Ecuadoran poison frog. J Am Chem Soc 114:3475–3478CrossRefGoogle Scholar
  27. Tomizawa M, Latli B, Casida JE (1996) Novel neonicotinoid-agarose affinity column for Drosophila and Musca nicotinic acetylcholine receptors. J Neurochem 67:1667–1676Google Scholar

Copyright information

© Springer Japan 1999

Authors and Affiliations

  • Richard A. Glennon
    • 1
  • Małgorzata Dukat
    • 1
  1. 1.Department of Medicinal ChemistryVirginia Commonwealth UniversityRichmondUSA

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