Hydroxy Metabolites of the Alzheimer's Drug Candidate 3-[(2,4-Dimethoxy)Benzylidene]-Anabaseine Dihydrochloride (GTS-21): Their Molecular Properties, Interactions with Brain Nicotinic Receptors, and Brain Penetration (original) (raw)

3-[(2,4-Dimethoxy)benzylidene]-anabaseine dihydrochloride (DMXBA; , an Alzheimer's drug candidate, selectively stimulates ␣7 nicotinic acetylcholine receptors. It rapidly enters the brain after oral administration and enhances cognitive behavior. Less than 1% of orally administered DMXBA is recovered in the urine. We report the identification and characterization of the major phase I metabolites of this drug candidate. Three hydroxy metabolites were generated in vitro by hepatic microsomal O-dealkylation of the two methoxy substituents on the benzylidene ring. They were also found in plasma of rats after oral administration, but at significantly lower concentrations relative to the parent compound. The metabolites displayed similar binding affinities and partial agonist potencies at rat brain ␣7 receptors. However, each displayed a higher efficacy than DMXBA for stimulating rat and human ␣7 receptors.