title: 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.
abstract: 2-Methyl-3-(2(S)-pyrrolidinylmethoxy)pyridine, ABT-089 (S-4), a member of the 3-pyridyl ether class of nicotinic acetylcholine receptor (nAChR) ligands, shows positive effects in rodent and primate models of cognitive enhancement and a rodent model of anxiolytic activity and possesses a reduced propensity to activate peripheral ganglionic type receptors. The profiles of S-4, its N-methyl analogue, and the corresponding enantiomers across several measures of cholinergic channel function in vitro and in vivo are presented, together with in vitro metabolism and in vivo bioavailability data. On the basis of its biological activities and favorable oral bioavailability, S-4 is an attractive candidate for further evaluation as a treatment for cognitive disorders.
authors.affiliation: Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
authors.forename: N H
authors.initials: NH
authors.lastname: Lin
authors.forename: D E
authors.initials: DE
authors.lastname: Gunn
authors.forename: K B
authors.initials: KB
authors.lastname: Ryther
authors.forename: D S
authors.initials: DS
authors.lastname: Garvey
authors.forename: D L
authors.initials: DL
authors.lastname: Donnelly-Roberts
authors.forename: M W
authors.initials: MW
authors.lastname: Decker
authors.forename: J D
authors.initials: JD
authors.lastname: Brioni
authors.forename: M J
authors.initials: MJ
authors.lastname: Buckley
authors.forename: A D
authors.initials: AD
authors.lastname: Rodrigues
authors.forename: K G
authors.initials: KG
authors.lastname: Marsh
authors.forename: D J
authors.initials: DJ
authors.lastname: Anderson
authors.forename: J J
authors.initials: JJ
authors.lastname: Buccafusco
authors.forename: M A
authors.initials: MA
authors.lastname: Prendergast
authors.forename: J P
authors.initials: JP
authors.lastname: Sullivan
authors.forename: M
authors.initials: M
authors.lastname: Williams
authors.forename: S P
authors.initials: SP
authors.lastname: Arneric
authors.forename: M W
authors.initials: MW
authors.lastname: Holladay
mesh_terms: D000284:Administration, Oral; D000470:Alkaloids / Q000378:metabolism; D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001392:Azocines; D001682:Biological Availability; D002038:Bungarotoxins / Q000378:metabolism; D002460:Cell Line; D003071:Cognition / Q000187:drug effects*; D004285:Dogs; D000882:Haplorhini; D006801:Humans; D007035:Hypothermia; D007555:Isoxazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008024:Ligands; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D011597:Psychomotor Performance / Q000187:drug effects; D011759:Pyrrolidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011807:Quinolizines; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012413:Rubidium / Q000378:metabolism; D013329:Structure-Activity Relationship; D000093843:Quinolizidine Alkaloids
chemical_list: D000470:Alkaloids; D014151:Anti-Anxiety Agents; D001392:Azocines; D002038:Bungarotoxins; D007555:Isoxazoles; D008024:Ligands; D011759:Pyrrolidines; D011807:Quinolizines; D011978:Receptors, Nicotinic; D012413:Rubidium; C088383:3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole; C004712:cytisine; D000093843:Quinolizidine Alkaloids