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)
Related papers
Behavioural Brain Research, 2000
A large decrease in brain nicotinic receptor levels occurs in Alzheimer's disease, relative to muscarinic and other receptors. Neurons possessing high affinity nicotinic receptors seem particularly vulnerable. The low affinity nicotinic receptors which selectively bind a-bungarotoxin are not significantly affected. The major nicotinic receptor subtype which binds this toxin is a homo-oligomer composed of a7 subunits. Due to its exceptionally high calcium ion selectivity, this particular receptor can be considered as a ligand-gated calcium channel. a7 receptors are found in regions of the brain which are important for cognition, including cerebral cortex and hippocampus. Hippocampal receptors are largely confined to GABAergic interneurons. a7 receptors seem less likely than a4-b2 receptors to be up-regulated in number and down-regulated in function as a result of chronic agonist exposure. A family of nicotinic agonists based upon the marine animal toxin anabaseine have been synthesized and investigated. One of these compounds, DMXBA [3-(2,4-dimethoxybenzylidene)-anabaseine; code name GTS-21] has displayed promising characteristics during phase I clinical tests. In the rat DMXBA is selectively agonistic upon a7 nicotinic receptors. In addition it is a moderately potent antagonist at a4-b2 receptors. DMXBA enhances a variety of cognitive behaviors in mice, monkeys, rats and rabbits. It also displays neuroprotective activity upon cultured neuronal cells exposed to b-amyloid or deprived of NGF. The compound is much less toxic than nicotine and does not affect autonomic and skeletal muscle systems at doses which enhance cognitive behavior. Phase I clinical tests indicate that large doses can be safely administered orally without adverse effects. Psychological tests on healthy young male subjects indicate a positive effect of DMXBA on some measures of cognition. While DMXBA is a much weaker partial agonist on human a7 receptors than upon rat a7 receptors, its 4-hydroxy metabolite has been shown to have excellent efficacy on both receptors. Thus, some of the physiological and behavioral effects of GTS-21 may be due to the actions of this primary metabolite.
The Journal of pharmacology and experimental therapeutics, 1998
3-(2,4-dimethoxybenzylidene)anabaseine (GTS-21) is a selective partial agonist for rat alpha-7 nicotine receptors with reportedly much lower efficacy for human alpha-7 receptors. Because this drug improves memory-related performance in nonhuman primates, and is presently in a clinical trial for Alzheimer's disease, we investigated the potential effects of its primary human metabolite, 3-(4-hydroxy, 2-methoxy-benzylidene)anabaseine) on human as well as rat nicotinic acetylcholine receptor. 4OH-GTS-21 exhibited a similar level of efficacy for both rat and human alpha-7 receptors expressed in Xenopus oocytes. It displaced high affinity [125I]alpha-bungarotoxin binding to human SK-N-SH cell-membranes (Ki 0.17 microM) and rat PC12 cell-membranes (Ki 0.45 microM). GTS-21 also displaced [125I]alpha-bungarotoxin binding to PC12 cell membranes with high potency (Ki 0.31 microM), but was much less potent in this regard in SK-N-SH cells (23 microM). 4OH-GTS-21 produced less residual inhibi...
Invertebrate Neuroscience, 1997
Naturally occurring toxins can often serve as useful chemical tools for investigating signalling processes in nervous and other systems. Tetrodotoxin and alpha-bungarotoxin are prime examples of toxins which are widely used in neurobiological research. Some toxins may also become molecular models for designing new drugs. Usually drugs are small, non-peptide molecules, as these display better bioavailability, longer durations of action and are less likely to generate immune responses. The relatively large size and conformational flexibility of peptides and protein toxins makes them more challenging molecular models for rational drug design. This article considers a marine invertebrate toxin, anabaseine, and describes how manipulation of the structure of this alkaloid has provided a drug candidate which selectively stimulates mammalian brain alpha7 nicotinic receptors. Numerous anabaseine analogs were synthesized and subjected to a variety of pharmacological, behavioral and toxcicological tests. This led to the choice of GTS-21 (also known as 3-(2,4-dimethoxybenzyl!dene)-anabaseine or DMXBA), as a drug candidate for the treatment of Alzheimer's dementia. The chemical and pharmacological properties of GTS-21 are compared with those of the initial lead compound, anabaseine.
Journal of Pharmacology and Experimental Therapeutics
para-Methyl-4-methylaminorex (4,49-DMAR) is a phenethylamine derivative with psychostimulant activity whose abuse has been associated with several deaths and a wide range of adverse effects. We recently validated a high-performance liquid chromatography-tandem mass spectrometry method to measure the compound's concentrations in plasma, and we applied it to describe the pharmacokinetic properties of 4,49-DMAR after a single dose in rats. In this study, we investigated the brain disposition and metabolism of cis-4,49-DMAR after intraperitoneal injection as well as its central behavioral effects. Locomotor activity increased after a single injection of 10 mg/kg, peaking at 2 hours and disappearing at 5 hours; in these conditions, brain absorption was very rapid, (t max 5 30-60 minutes) and large (brain-to-plasma ratio 5 24); the half-life was approximately 50 minutes. After 14 daily doses, the compound's effect on locomotor activity was greater (approximately 20% compared with the effect after the first dose), but not for pharmacokinetic reasons. Using high-resolution mass spectrometry, we also identified four metabolites of cis-4,49-DMAR in the plasma and brain of treated rats. Semiquantitative analysis indicated low brain permeability and very low brain concentrations, suggesting that these metabolites do not contribute to central behavioral effects; however, the metabolite originating from oxidation of the paramethyl group (M2) persisted in the plasma longer and at higher concentrations than the parent molecule and could be used to evaluate drug intake in human consumers. Finally, we describe the rewarding effect of cis-4,49-DMAR in the conditioning place preference test, suggesting a high risk of addiction in humans.
Novel long-acting antagonists of muscarinic ACh receptors
British Journal of Pharmacology
The aim of this study was to develop potent and long-acting antagonists of muscarinic ACh receptors. The 4-hexyloxy and 4butyloxy derivatives of 1-[2-(4-oxidobenzoyloxy)ethyl]-1,2,3,6-tetrahydropyridin-1-ium were synthesized and tested for biological activity. Antagonists with long-residence time at receptors are therapeutic targets for the treatment of several neurological and psychiatric human diseases. Their long-acting effects allow for reduced daily doses and adverse effects.
Marine Drugs
Three major forms of the nicotinic agonist toxin anabaseine (cyclic iminium, cyclic imine and the monocationic open-chain ammonium-ketone) co-exist in almost equal concentrations at physiological pH. We asked the question: Which of these forms is pharmacologically active? First, we investigated the pH dependence of anabaseine inhibition of [3H]-methylcarbamylcholine binding at rat brain α4β2 nicotinic acetylcholine receptors (nAChRs). These experiments indicated that one or both monocationic forms interact with the orthosteric binding site for ACh. However, since they occur at equal concentrations near physiological pH, we employed another approach, preparing a stable analog of each form and examining its agonist activities and binding affinities at several vertebrate brain and neuromuscular nAChRs. Only 2-(3-pyridyl)-1,4,5,6-tetrahydropyrimidine monohydrogen chloride (PTHP), the cyclic iminium analog, displayed nAChR potencies and binding affinities similar to anabaseine. The cycli...
Marine Drugs, 2006
Nemertines are a phylum of carnivorous marine worms that possess a variety of alkaloidal, peptidic or proteinaceous toxins that serve as chemical defenses against potential predators. The hoplonemertines additionally envenomate their prey with a mixture of proboscis alkaloids delivered with the help of a calcareous stylet that punctures the skin of the victim. Anabaseine, the first of these alkaloids to be identified, stimulates a wide variety of animal nicotinic acetylcholine receptors (AChRs), especially the neuromuscular [e.g., α1 2 β1γδ (embryogenic) or α1 2 β1γε (adult)] and α7 AChRs that are inhibited by the snake peptide α-bungarotoxin. A synthetic derivative, 3-(2,4-Dimethoxybenzylidene)-Anabaseine (DMXBA; also called GTS-21), improves memory in experimental animals and humans and is currently in clinical trials to determine whether it can ameliorate cognitive problems associated with schizophrenia. Here we summarize present knowledge concerning the chemistry and mechanisms of action of these two substances (anabaseine and DMXBA) on AChRs, especially those found in the mammalian brain.
Theoretical and molecular modeling studies have been conducted for understanding the details of how 3-[(2,4-dimethoxy)benzylidene]-anabaseine dihydrochloride (GTS-21) and its metabolism derivatives bind with the receptor of a7 nicotinic acetylcholine dimer. Good accordance with experimental results has been achieved. It was found that the van der Waals repulsion makes the dominant contribution to the binding energy. GTS-21 and its metabolites are apparently too large for the binding sites of the a7 dimer. To improve the effectiveness of the drug, a possible approach is to reduce its volume while maintaining the presence of the active groups. Our studies, in combination with experimental studies, will lead to a promising basis for practical drug design against AlzheimerÕs disease.