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

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 (EC(50) = 214 +/- 30 mu M and 52 +/- 4 mu M, respectively) while the efficacy of ABT-418 was not significantly different 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 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 stud ies 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. (C) 1995 Wiley-Liss, Inc.