STRUCTURE-ACTIVITY STUDIES ON 2-METHYL-3-(2(S)-PYRROLIDINYLMETHOXY)PYRIDINE (ABT-089) - AN ORALLY BIOAVAILABLE 3-PYRIDYL ETHER NICOTINIC ACETYLCHOLINE-RECEPTOR LIGAND WITH COGNITION-ENHANCING PROPERTIES

2-Methyl-3-(2(S)-pyrrolidinylmethoxy)pyridine, ABT-089 (S-4), a member of the 3-pyridyl ether class of nicotinic acetylcholine receptor (nAC hR) ligands, shows positive effects in rodent and primate models of co gnitive enhancement and a rodent model of anxiolytic activity and poss esses a reduced propensity to activate peripheral ganglionic type rece ptors. The profiles of S-4, its N-methyl analogue, and the correspondi ng enantiomers across several measures of cholinergic channel function in vitro and in vivo are presented, together with in vitro. metabolis m and in vivo bioavailability data. On the basis of its biological act ivities and favorable oral bioavailability, S-4 is an attractive candi date for further evaluation as a treatment for cognitive disorders.