ABT-089 [2-methyl-3-(2-(s)-pyrrolidinylmethoxy) pyridine dihydrochloride]: Discriminative stimulus properties and electrophysiological actions

ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy) pyridine dihydrochloride] is a novel cholinergic channel modulator (ChCM) with cognitive-enhancing and neuroprotective activities. Experiments were conducted to determine the discriminative stimulus properties of ABT-089 in comparison with (–)-nicotine. While rats were able to discriminate (–)-nicotine (1.9 μmol/kg s.c.) from saline in 43 ± 1.9 days, they were not able to discriminate ABT-089 (19 or 62 μmol/kg s.c.) from a saline solution after 64 days of training. In rats trained to discriminate 1.9 μmol/kg (–)-nicotine from saline, ABT-089 induced a reduced maximal generalization (up to 52% with 6.2–190 μmol/kg, s.c.) and was 100 times less potent than (–)-nicotine to induce the cue. A-94224.3, the R-enantiomer of ABT-089, induced a saline response at 62 μmol/kg in nicotine-trained rats. The effects of (–)-nicotine and ABT-089 were completely blocked by the cholinergic channel blocker, mecamylamine (15 μmol/kg). Consistent with its oral bioavailability, ABT-089 exhibited comparable effects in (–)-nicotine-trained rats after oral administration. Electrophysiological studies in dopamine-containing neurons in the ventral tegmental area indicate that ABT-089 is a weak partial agonist that can also block the excitatory actions of (–)-nicotine. The low intrinsic efficacy of ABT-089 to cross-generalize with (–)-nicotine is consistent with the minimal activity of the compound at the ganglia-like α3 subtype. Drug Dev. Res. 40:259–266, 1997. © 1997 Wiley-Liss, Inc.