GANGLIONIC NICOTINIC ACETYLCHOLINE-RECEPTOR ACTIVATION BY THE NOVEL AGONIST ABT-418

ABT-418 was functionally characterized as a neuronal nicotinic acetylc holine receptor (nAChR) channel agonist using preparations that contai n nAChRs characteristic of the ganglionic subtypes. In PC12 cells, ABT -418, like (-)nicotine, activated an inward current that decayed withi n seconds in the continued presence of agonist. ABT-418 was 4-fold les s potent than (-)nicotine (EC(50) = 214 +/- 30 mu M and 52 +/- 4 mu M, respectively) while the efficacy of ABT-418 was not significantly dif ferent from (-)nicotine when the peak response amplitude was measured. Responses to 300 mu M ABT-418 were reversibly inhibited 81 +/- 3% by 10 mu M mecamylamine, 38 +/- 1% by 10 mu M dihydro-beta-erythroidine, and 82 +/- 2% by 100 mu M dihydro-beta-erythroidine, These nAChR antag onists affected the response to (-)nicotine similarly. Furthermore, re sponses 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-4 18 (1.18 +/- 0.20) was smaller than that for (-)nicotine (1.77 +/- 0.1 8), and high concentrations of ABT-418 appeared to elicit a more rapid ly decaying response than did (-)nicotine. In the rat superior cervica l sympathetic ganglion also, ABT-418 was 2.5-fold less potent than (-) nicotine in blocking nicotinic transmission, presumably through nicoti nic receptor desensitization. These stud ies provide the most direct e vidence that ABT-418 activates nicotinic cholinergic channels, and sug gest that ABT-418 would have reduced potency compared to (-)nicotine i n peripheral ganglia, consistent with the reduced side effect liabilit y of this novel nAChR agonist. (C) 1995 Wiley-Liss, Inc.