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 (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.
Lin
N H
NH
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
Gunn
D E
DE
Ryther
K B
KB
Garvey
D S
DS
Donnelly-Roberts
D L
DL
Decker
M W
MW
Brioni
J D
JD
Buckley
M J
MJ
Rodrigues
A D
AD
Marsh
K G
KG
Anderson
D J
DJ
Buccafusco
J J
JJ
Prendergast
M A
MA
Sullivan
J P
JP
Williams
M
M
Arneric
S P
SP
Holladay
M W
MW
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
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