COMPARATIVE PHARMACOLOGY OF NICOTINE AND ABT-418, A NEW NICOTINIC AGONIST

ABT-418, a novel cholinergic ligand, was reported to possess potent co gnitive-enhancing and anxiolytic properties in animal models with redu ced side effects (Decker et al. 1994; Garvey et al. 1994) suggesting s electivity of effects. In this study, the binding properties of ABT-41 8 to [H-3]-nicotine sites were evaluated and its pharmacology investig ated in different tests in laboratory animals. ABT-418 binds with high affinity to H-3-nicotine binding sites in the brain with, however, a K-i (6 nM) less than that of nicotine (four-fold). In addition, it act s as a full nicotinic agonist in producing hypomotility, hypothermia a nd antinociception in mice and engendering nicotine-like responding in rat drug discrimination. The potency of ABT-418 is three to four time s less than that of nicotine in all of the animal models, except for h ypothermia. In addition, its behavioral effects are completely blocked by mecamylamine, a non-competitive nicotinic antagonist. Although act ivation of nicotinic receptors by ABT-418 produced several behavioral and pharmacological effects, our results do not suggest high selectivi ty 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 so me of these tests that produced effects at low doses (Decker et al. 19 94) and additional pharmacological studies are needed to establish its selectivity at multiple nicotinic receptors.