Metabolism and disposition of GTS-21, a novel drug for Alzheimer's disease

Azuma, Ryotaro; Komuro, Masahito; Korsch, BH; André, J. A. M. Van Der Ven; Onnagawa, O.; Black, S L; Mathews, James

doi:10.1080/004982599238362

Cited by 27 publications

(15 citation statements)

References 10 publications

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“…3) in the rat are apparently different. This interpretation is consistent with the different storage stabilities of the two enzyme activities and with observed effects of selective cytochrome P450 inhibitors (Azuma et al, 1999;Kem et al, unpublished results).…”

Section: Discussionsupporting

confidence: 75%

“…A major difference between our biotransformation data and those of Azuma et al (1999) pertained to 2-OH-MBA, which they did not detect in vitro or in vivo. However, they isolated its glucuronide from urine.…”

Section: Discussionmentioning

confidence: 61%

“…The relative importance of the two potential pathways depends on DMXBA concentration at the sites of biotransformation as well as the concentrations and Michaelis-Menten kinetic properties of the cytochromes P450 involved in the two Odemethylations. The observed concentrations of the dihydroxy metabolite (2,4-DiOH-BA) were quite limited, both in vitro and in vivo, apparently because the two monohydroxylated metabolites are readily glucuronidated (Azuma et al, 1999). (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…It is known that 4-OH-MBA is readily glucuronidated (Azuma et al, 1999;Kitagawa et al, 2003;Kem et al, unpublished results). The plasma time profiles (Fig.…”

Section: Discussionmentioning

confidence: 99%

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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

Kem

Mahnir

Prókai³

et al. 2004

Mol Pharmacol

107

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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.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 61%

Section: Resultsmentioning

confidence: 99%

“…It is known that 4-OH-MBA is readily glucuronidated (Azuma et al, 1999;Kitagawa et al, 2003;Kem et al, unpublished results). The plasma time profiles (Fig.…”

Section: Discussionmentioning

confidence: 99%

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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

Kem

Mahnir

Prókai³

et al. 2004

Mol Pharmacol

107

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“…The in vivo/in vitro correlation of penetration profiles of the model drug, GTS-21, [3][4][5] have also been investigated on the basis of bi-layer skin pharmacokinetic model.…”

mentioning

confidence: 99%

Prediction of Plasma Concentration of GTS-21 in Hairless Rats Following Monolithic Transdermal Delivery.

Kawamata

Tojo²

2002

Biological & Pharmaceutical Bulletin

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One of the most characteristic features of transdermal therapeutic systems (TTS) is a constant long-term delivery bypassing the first pass metabolism.1) This reduces the risk of side effects and prolongs the interval of administration. However, recent study has revealed that the constant therapeutic plasma concentration is not always effective for drugs such as nitroglycerin.2) It is also necessary to utilize the drug more effectively so that the dose is minimized. Under these circumstances, the rate of penetration of the skin may decrease with time because of the decreased partitioning on the skin surface.In this study, we have proposed a simple approach to predict the plasma concentration following monolithic transdermal delivery with low loading dose. The in vivo/in vitro correlation of penetration profiles of the model drug, GTS-21, [3][4][5] have also been investigated on the basis of bi-layer skin pharmacokinetic model. MATERIALS AND METHODSMaterials GTS-21 [(E)-3-(2,4-dimethoxybenzylidine)-3,4,5,6-tetrahydro-2,3Ј-bipyridine dihydrochloride] was supplied by Kobe Natural Products and Chemicals (Kobe, Japan). Polyethylene glycol 400, isopropyl myristate and sodium azide were purchased from Wako Pure Chemical Industries (Osaka, Japan). Other reagents and solvents were commercially available and of reagent grade or better.Preparation of GTS-21 Free-Base TTS GTS-21 freebase was prepared from GTS-21 by extraction with ethyl acetate at alkaline pH. The prepared compound was identified as free-base by NMR analysis. GTS-21 free-base was mixed with isopropyl myristate, toluene and silicone elastomer BIO-PSA Q7-4501 (Dow Corning Asia, Tokyo, Japan). This mixture was spread on a polyester release liner by a Baker type applicator (Tester Sangyo, Tokyo, Japan) and dried in an oven at 115°C for 1 min. Subsequently, the adhesive layer on the release liner was laminated with a polyethylene backing. The thickness of the adhesive layer was adjusted to between 50 and 60 mm. The content of GTS-21 free-base was controlled at 0.172 mg/cm 2 . The monolithic TTS devices used for GTS-21 free-base were cut to for each study.In Vitro Skin Permeation Experiment Excised abdominal skin from male WBN hairless rats (200-220 g, Ishikawa laboratory animal, Saitama, Japan) was used. The abdominal skin was shaven with a BS 5 585 shaver (Brown, Kanagawa, Japan) before the experiment. Either intact skin or stripped skin was mounted on a vertical diffusion cell (Ishii Shoten, Tokyo, Japan). The stripped skin was prepared by stripping the stratum corneum with cellophane tape (Nichiban, Tokyo, Japan) 20 times before excision. The receptor fluid, a 40% (v/v) aqueous solution of polyethylene glycol 400, was maintained at 38.0°C. GTS-21 free-base TTS (2.83 cm 2 ) was placed on the skin and the system was fixed with a cell cap and clamp. The receptor fluid (200 ml) was sampled periodically and the drug concentration was analyzed immediately by HPLC. The assay conditions were as follows: sample size, 20 ml; column, Develosil ODS-HG-5 (Nomura Chemical, ...

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Cognition Enhancers

Jr.

Kinney

2003

Burger's Medicinal Chemistry and Drug Discovery

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Very little can be done to abate or control the progression of dementia, a clinical syndrome most commonly encountered later in life and manifested by impairments in cognition, language, and memory. The percentage of the world's elderly population is increasing, and so too is the need for effective pharmaceutical interventions for dementias such as Alzheimer's disease (AD), age‐associated memory impairment (AAMI), multi‐infarct dementia (MID), vascular dementia, and Parkinsonian dementia. Advances have been made in understanding the etiology of these diseases, but much remains to be discovered. In this chapter we have focused on the development of several therapeutic approaches that have in common the ability to modulate gated ion channels, and as such, have the potential to affect multiple neurotransmitter systems. Specifically, we discuss the structure‐activity relationship (SAR) and behavioral outcome for ligands interacting with the (1) γ‐aminobutyric acid subtype A benzodiazepine receptor (GABA A /BzR); (2) nicotinic acetylcholine receptor (nAChR); (3) serotonin subtype 3 receptor (5‐HT 3 R); and (4) the potassium M‐channel.

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Metabolism and disposition of GTS-21, a novel drug for Alzheimer's disease

Cited by 27 publications

References 10 publications

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

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

Prediction of Plasma Concentration of GTS-21 in Hairless Rats Following Monolithic Transdermal Delivery.

Cognition Enhancers

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