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.
MeSH terms
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Administration, Oral
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Alkaloids / metabolism
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Animals
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Anti-Anxiety Agents / chemistry
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Anti-Anxiety Agents / metabolism
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Anti-Anxiety Agents / pharmacology*
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Azocines
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Biological Availability
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Bungarotoxins / metabolism
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Cell Line
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Cognition / drug effects*
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Dogs
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Haplorhini
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Humans
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Hypothermia
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Isoxazoles / chemistry
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Isoxazoles / metabolism
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Isoxazoles / pharmacology*
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Ligands
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Maze Learning / drug effects
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Mice
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Molecular Structure
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Psychomotor Performance / drug effects
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Pyrrolidines / chemistry
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Pyrrolidines / metabolism
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Pyrrolidines / pharmacology*
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Quinolizines
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Receptors, Nicotinic / metabolism*
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Rubidium / metabolism
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Structure-Activity Relationship
Substances
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Alkaloids
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Anti-Anxiety Agents
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Azocines
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Bungarotoxins
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Isoxazoles
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Ligands
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Pyrrolidines
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Quinolizines
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Receptors, Nicotinic
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3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole
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cytisine
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Rubidium