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 dihydrochlori de) is a novel cholinergic channel modulator (ChCM) with cognitive-enh ancing and neuroprotective activities. Experiments were conducted to d etermine the discriminative stimulus properties of ABT-089 in comparis on with (-)-nicotine. While rats were able to discriminate (-)-nicotin e (1.9 mu mol/kg s.c.) from saline in 43 +/- 1.9 days, they were not a ble to discriminate ABT-089 (19 or 62 mu mol/kg s.c.) from a saline so lution after 64 days of training. In rats trained to discriminate 1.9 mu mol/kg (-)-nicotine from saline, ABT-089 induced a reduced maximal generalization (up to 52% with 6.2-190 mu mol/kg, s.c) and was 100 tim es less potent than (-)-nicotine to induce the cue. A-94224.3, the R-e nantiomer of ABT-089, induced a saline response at 62 mu mol/kg in nic otine-trained rats. The effects of (-)-nicotine and ABT-089 were compl etely blocked by the cholinergic channel blocker, mecamylamine (15 mu mol/kg). Consistent with its oral bioavailability, ABT-089 exhibited c omparable effects in (-)-nicotine-trained rats after oral administrati on. Electrophysiological studies in dopamine-containing neurons in the ventral tegmental area indicate that ABT-089 is a weak partial agonis t 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-l ike alpha 3 subtype. Drug Dev. Res. 40:259-266, 1997. (C) 1997 Wiley-L iss, Inc.