The brain alpha7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer's disease: studies with DMXBA (GTS-21).
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 alpha-bungarotoxin are not significantly affected. The major nicotinic receptor subtype which binds this toxin is a homo-oligomer composed of alpha7 subunits. Due to its exceptionally high calcium ion selectivity, this particular receptor can be considered as a ligand-gated calcium channel. Alpha7 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. Alpha7 receptors seem less likely than alpha4-beta2 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 alpha7 nicotinic receptors. In addition it is a moderately potent antagonist at alpha4-beta2 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 beta-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 alpha7 receptors than upon rat alpha7 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.
Kem
W R
WR
Department of Pharmacology and Experimental Therapeutics, University of Florida College of Medicine, Gainesville 32610-0267, USA. kem@pharmacology.ufl.edu
D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D001597:Benzylidene Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D002540:Cerebral Cortex / Q000187:drug effects; D017321:Clinical Trials, Phase I as Topic; D005260:Female; D006624:Hippocampus / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D009483:Neuropsychological Tests; D018722:Nicotinic Agonists / Q000009:adverse effects / Q000627:therapeutic use*; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D011817:Rabbits; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects*; D064569:alpha7 Nicotinic Acetylcholine Receptor
D001597:Benzylidene Compounds; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C088936:3-(2,4-dimethoxybenzylidene)anabaseine