Ganglionic nicotinic acetylcholine receptor activation by the novel agonist ABT‐418

C. A. Briggs, M. L. Hughes, Lisa M Monteggia, T. Giordano, D. Donnelly-Roberts, S. P. Arneric

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

ABT‐418 was functionally characterized as a neuronal nicotinic acetylcholine receptor (nAChR) channel agonist using preparations that contain nAChRs characteristic of the ganglionic subtypes. In PC12 cells, ABT‐418, like (−)nicotine, activated an inward current that decayed within seconds in the continued presence of agonist. ABT‐418 was 4‐fold less potent than (−)nicotine (EC50 = 214 ± 30 μM and 52 ± 4 μM, respectively) while the efficacy of ABT‐418 was not significantly different from (−)nicotine when the peak response amplitude was measured. Responses to 300 μM ABT‐418 were reversibly inhibited 81 ± 3% by 10 μM mecamylamine, 38 ± 1% by 10 μM dihydro‐β‐erythroidine, and 82 ± 2% by 100 μM dihydro‐β‐erythroidine. These nAChR antagonists affected the response to (−)nicotine similarly. Furthermore, responses to maximal concentrations of ABT‐418 (3 mM) and (−)nicotine (1 mM) were not additive, consistent with ABT‐418 and (−)nicotine acting through the same receptor(s). However, the Hill coefficient for ABT‐418 (1.18 ± 0.20) was smaller than that for (−)nicotine (1.77 ± 0.18), and high concentrations of ABT‐418 appeared to elicit a more rapidly decaying response than did (−)nicotine. In the rat superior cervical sympathetic ganglion also, ABT‐418 was 2.5‐fold less potent than (−)nicotine in blocking nicotinic transmission, presumably through nicotinic receptor desensitization. These studies provide the most direct evidence that ABT‐418 activates nicotinic cholinergic channels, and suggest that ABT‐418 would have reduced potency compared to (−)nicotine in peripheral ganglia, consistent with the reduced side effect liability of this novel nAChR agonist. © Wiley‐Liss, Inc.

Original languageEnglish (US)
Pages (from-to)39-46
Number of pages8
JournalDrug Development Research
Volume34
Issue number1
DOIs
StatePublished - Jan 1995

Keywords

  • PC12 cells
  • electrophysiology
  • ganglionic stimulants
  • nicotine
  • nicotinic receptors

ASJC Scopus subject areas

  • Drug Discovery

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  • Cite this

    Briggs, C. A., Hughes, M. L., Monteggia, L. M., Giordano, T., Donnelly-Roberts, D., & Arneric, S. P. (1995). Ganglionic nicotinic acetylcholine receptor activation by the novel agonist ABT‐418. Drug Development Research, 34(1), 39-46. https://doi.org/10.1002/ddr.430340107