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

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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.

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

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Keywords

  • Electrophysiology
  • Ganglionic stimulants
  • Nicotine
  • Nicotinic receptors
  • PC12 cells

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

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