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

Abstract

3-[(2,4-Dimethoxy)benzylidene]-anabaseine dihydrochloride (DMXBA; GTS-21), 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.Like DMXBA, the metabolites were weak antagonists at ␣ 4 ␤ 2 receptors. The predicted conformations of the metabolites were nearly identical with that of DMXBA. Ionization of the tetrahydropyridyl nitrogen was essential for high-affinity binding of DMXBA to the ␣7 receptor. The hydroxy metabolites were much more polar than DMXBA, derived from their experimentally estimated octanol/water partition coefficients, and they entered the brain much less readily than DMXBA. Their contributions to the behavioral effects of orally administered DMXBA, if any, would probably be very small during short-term administration. Benzylidene anabaseines pharmacologically similar to the hydroxy metabolites, but which enter the brain more readily, may provide greater stimulation of ␣7 receptors in the whole organism.

Spectroscopic Analysis of Benzylidene Anabaseine Complexes with Acetylcholine Binding Proteins as Models for Ligand−Nicotinic Receptor Interactions

“…This allowed for an estimate of the apparent pK a value for the tetrahydropyridine nitrogen (Table 2) with results in reasonable agreement with previously reported values (10).…”

Activation and Desensitization of Nicotinic α7-type Acetylcholine Receptors by Benzylidene Anabaseines and Nicotine

“…1; Table 1). Previously characterized compounds included diMeOBA (also known as GTS-21 and DMXBA), as well as its hydroxy metabolites Kem et al, 2004). Published data for these compounds are given in Table 1, along with new data on other disubstituted and monosubstituted BA compounds.…”

“…BA compounds were synthesized by reaction of anabaseine dihydrochloride with the appropriate benzaldehyde as reported previously (Kem, 1971;Zoltewicz et al, 1993;Kem et al, 2004). They were purified by silica gel chromatography, and their purity was established by NMR.…”

Compartmentalization and Antiviral Effect of Efavirenz Metabolites in Blood Plasma, Seminal Plasma, and Cerebrospinal Fluid

“…Weak acids have previously been demonstrated to accumulate in prostatic fluid by iontrapping mechanisms (Winningham et al, 1968). Mono-oxygenation or dioxygenation of a compound can impact both the acid-dissociation constant and lipophilicity (partition coefficient, logP) of a molecule, which can have a marked impact on the compound's disposition (Mack and Bönisch, 1979;Kem et al, 2004). In oxidative metabolism, the logP is typically shown to reduce for a compound as it is transformed to be more hydrophilic (Manners et al, 1988), which also impacts the acidity and basicity (pKa) of a compound.…”