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Psychopharmacology

, Volume 120, Issue 4, pp 483–490 | Cite as

Comparative pharmacology of nicotine and ABT-418, a new nicotinic agonist

  • M. I. Damaj
  • K. R. Creasy
  • S. P. Welch
  • J. A. Rosecrans
  • M. D. Aceto
  • B. R. Martin
Original Investigation

Abstract

ABT-418, a novel cholinergic ligand, was reported to possess potent cognitive-enhancing and anxiolytic properties in animal models with reduced side effects (Decker et al. 1994; Garvey et al. 1994) suggesting selectivity of effects. In this study, the binding properties of ABT-418 to [3H]-nicotine sites were evaluated and its pharmacology investigated in different tests in laboratory animals. ABT-418 binds with high affinity to3H-nicotine binding sites in the brain with, however, a Ki (6 nM) less than that of nicotine (four-fold). In addition, it acts as a full nicotinic agonist in producing hypomotility, hypothermia and antinociception in mice and engendering nicotine-like responding in rat drug discrimination. The potency of ABT-418 is three to four times less than that of nicotine in all of the animal models, except for hypothermia. In addition, its behavioral effects are completely blocked by mecamylamine, a non-competitive nicotinic antagonist. Although activation of nicotinic receptors by ABT-418 produced several behavioral and pharmacological effects, our results do not suggest high selectivity of different effects as reported by Decker et al. (1994) and Garvey et al. (1994). However, it should be noted that we did not perform some of these tests that produced effects at low doses (Decker et al. 1994) and additional pharmacological studies are needed to establish its selectivity at multiple nicotinic receptors.

Key words

Nicotine ABT-418 Antinociception Hypothermia Locomotor activity Drug discrimination 

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References

  1. Aceto MD, Martin BR, Uwaydah IM, May EL, Harris LS, Izazola-Conde C, Dewey WL, Vincek WC (1979) Optically pure (+)-nicotine from (±)-nicotine and biological comparisons with (−)-nicotine. J Med Chem 22: 174–177Google Scholar
  2. Aceto MD, Bagley RS, Dewey WL, Fu T-C, Martin BR (1986) The spinal cord as a major site for the antinociceptive action of nicotine in the rat. Neuropharmacology 25: 1031–1036Google Scholar
  3. Aceto MD, Bowman ER, Harris LS, May EL (1994) Dependence studies of new compounds in the rhesus monkey, rat and mouse. NIDA Monogr 140: 103–178Google Scholar
  4. Arneric SP, Sullivan JP, Briggs CA, Donnelly-Roberts D, Anderson DJ, Raszkiewicz J, Hugues ML, Cadman ED, Adams P, Garvey DS, Wasicak JT, Williams M (1994) (S)-3-Methyl-5-(1-methyl-2-pyrrolidinyl) isoxazole (abt 418): a novel cholinergic ligand with cognition-enhancing and anxiolytic activities: II. In vitro characterization. J Pharmacol Exp Ther 270: 310–318Google Scholar
  5. Atwell L, Jacobson AE (1978) The search for less harmful analgesics. Lab Anim 7: 42–47Google Scholar
  6. Brioni JD, Kim DJB, Brodie MS, Decker MW, Arneric SP (1994a) ABT-418: discriminative stimulus properties and effect on ventral tegmental cell activity. Psychopharmacology (in press)Google Scholar
  7. Brioni JD, O'Neill AB, Kim DJB, Buckley MJ, Decker MW, Arneric SP (1994b) Anxiolytic-like effects of the novel cholinergic channel activator ABT-418. J Pharmacol Exp Ther 271: 353–361Google Scholar
  8. Corrigall WA, Coen KM (1989) Nicotine maintains robust self-administration in rats on a limited-access schedule. Psychopharmacology 99: 473–478Google Scholar
  9. D'Amour FE, Smith DL (1941) A method for determining loss of pain sensation. J Pharmacol Exp Ther 72: 74–79Google Scholar
  10. Decker M, Majchrzak M, Arneric S (1993) Effects of lobeline, a nicotinic receptor agonist, on learning and memory. Pharmacol Biochem Behav 45: 571–576Google Scholar
  11. Decker MW, Brioni JD, Sullivan JP, Buckley MJ, Radek RJ, Raszkiewicz JL, Kang CH, Kim DJB, Giardina WJ, Wasicak JT, Garvey DS, Williams M, Arneric SP (1994) (S)-3-Methyl-5-(1-methyl-2-pyrrolidinyl) isoxazole (abt 418): a novel cholinergic ligand with cognition-enhancing and anxiolytic activities: II. In vivo characterization. J Pharmacol Exp Ther 270: 319–328Google Scholar
  12. Dewey WL, Harris LS, Howes JS, Nuite JA (1970) The effect of various neurohormonal modulations on the activity of morphine and the narcotic antagonistsin taik-flick and phenylquinone test. J Pharmacol Exp Ther 175: 435–442Google Scholar
  13. Dukat M, Damaj MI, Glassco W, Dumas D, May EL, Martin BR, Glennon RA (1993) Epibatidine: a very high affinity nicotine-receptor ligand. Med Chem Res 4: 131–139Google Scholar
  14. Eddy NB, Leimbach D (1953) Synthetic analgesics. II. Dithienybutenyl-and benzomorphans. J Pharmacol Exp Ther 107: 385–939Google Scholar
  15. Garvey D, Decker M, Buckley M, Carrera G, Wasicak J, Brioni J, Sullivan J, Holladay M, Williams M (1994) Novel isoxazoles which interact with brain cholinergic channel receptors have intrinsic cognitive enhancing and anxiolytic activities. J Med Chem 37: 1055–1059Google Scholar
  16. Glassco W, Suchocki J, George C, Martin B, May E (1993) Synthesis, optical resolution, absolute configuration, and preliminary pharmacology of (+)- abd (−)-cis-2,3,3a,4,5,9b-hexahydro-1-methyl-1h-pyrrolo-3, 2-h] isoquinoline, a structural analog of nicotine. J Med Chem 36: 3381–3385Google Scholar
  17. Glassco W, May EL, Damaj MI, Martin BR (1994) In vivo and in vitro activity of someN-substituted (±)-nornicotine analogs. Med Chem Res 4: 273–282Google Scholar
  18. Glennon RA, Maarouf A, Fahmy S, Martin B, Fan F, Yousif M, Shafik RM, Malgorzata D (1993) Structure-affinity relationships of simple nicotine analogs. Med Chem Res 2: 546–551Google Scholar
  19. Hylden JL, Wilcox GL (1980) Intrathecal morphine in mice: a new technique. Eur J Pharmacol 67: 313–316Google Scholar
  20. Kachur JF, May EL, Awaya H, Egle Jr. JL, Aceto MD, Martin BR (1986) Pharmacological effects of 1,2,3,5,6,10b-hexahydropyrido[2, 3g]indolizine, a bridged-nicotine analog. Life Sci 38: 323–330Google Scholar
  21. Levin ED (1992) Nicotinic systems and cognitive function. Psychopharmacology 108: 417–431Google Scholar
  22. Litchfield ST, Wilcoxon F (1949) A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther 96: 99–113Google Scholar
  23. Martin BR (1986) Nicotine receptors in the central nervous system. In: Conn PM (ed) The receptors. Academic Press, New York, pp 393–415Google Scholar
  24. Martin TJ, Suchocki J, May EL, Martin BR (1990) Pharmacological evaluation of the antagonism of nicotine's central effects by mecamylamine and pempidine. J Pharmacol Exp Ther 254: 45–51Google Scholar
  25. Patrick J, Luetje C (1993) Pharmacological diversity of nicotine receptors. In: Korenman SG, Barchas JD (ed) Biological basis for substance abuse. Oxford University Press, N.Y., pp 81–95Google Scholar
  26. Reavill C, Jenner P, Kumar R, Stolerman IP (1988) High affinity binding of [3H] (−)-nicotine to rat brain membranes and its inhibition by analogues of nicotine. Neuropharmacology 27: 235–241Google Scholar
  27. Reavill C, Walther B, Stolerman IP, Testa B (1990) Behavioural and pharmacokinetic studies on nicotine, cytisine and lobeline. Neuropharmacology 29: 619–624Google Scholar
  28. Rosecrans JA (1989) Nicotine as a discriminative stimulus: a neurobiobehavioral approach to studying central cholinergic mechanisms. J Subst Abuse 1: 287–300Google Scholar
  29. Scimeca JA, Martin BR (1988) The effect of acute dyflos (DFP) treatment on [3H]nicotine binding to mouse brain homogenate. J Pharm Pharmacol 40: 793–797Google Scholar
  30. Stolerman IP (1990) Behavioural pharmacology of nicotine in animals. In: Wonnacott S, Russell MAH, Stolerman IP (ed) Nicotine psychopharmacology. Oxford University Press, New York, pp 278–306Google Scholar
  31. Tallarida RJ, Murray RB (1987) Manual of pharmacological calculations with computer programs, 2nd edn. Springer, New York, p 293Google Scholar
  32. Williams M, Sullivan JP, Arneric SP (1994) Neuronal nicotinic acetylcholine receptors. Drug New Perspect 7: 205–223Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • M. I. Damaj
    • 1
  • K. R. Creasy
    • 1
  • S. P. Welch
    • 1
  • J. A. Rosecrans
    • 1
  • M. D. Aceto
    • 1
  • B. R. Martin
    • 1
  1. 1.Department of Pharmacology and Toxicology, Medical College of VirginiaVirginia Commonwealth UniversityRichmondUSA

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