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ABT‐089 [2‐methyl‐3‐(2‐(s)‐pyrrolidinylmethoxy) pyridine dihydrochloride]: Discriminative stimulus properties and electrophysiological actions
Author(s) -
Brioni Jorge D.,
Kim David J.B.,
O'Neill Alyssa,
Brodie Mark S.,
Decker Michael W.,
Arneric Stephen P.
Publication year - 1997
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(199703)40:3<259::aid-ddr6>3.0.co;2-j
Subject(s) - nicotine , pharmacology , mecamylamine , chemistry , electrophysiology , saline , nicotinic agonist , agonist , cholinergic , anesthesia , endocrinology , medicine , biochemistry , receptor
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.