From the Cover: Small molecule blockers of the Alzheimer Aβ calcium channel potently protect neurons from Aβ cytotoxicity |
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| Authors: | Juan Carlos Diaz Olga Simakova Kenneth A. Jacobson Nelson Arispe Harvey B. Pollard |
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| Affiliation: | aDepartment of Anatomy, Physiology and Genetics, Uniformed Services University School of Medicine, Bethesda, MD 20814; and ;bMolecular Recognition Section, Laboratory of Biooganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 |
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| Abstract: | Alzheimer's disease (AD) is a common, chronic neurodegenerative disease that is thought to be caused by the neurotoxic effect of the Amyloid beta peptides (Aβ). We have hypothesized that the intrinsic Aβ calcium channel activity of the oligomeric Aβ polymer may be responsible for the neurotoxic properties of Aβ, and that Aβ channel blockers may be candidate AD therapeutics. As a consequence of a rational search paradigm based on the model structure of the Aβ channel, we have identified two compounds of interest: MRS2481 and an enatiomeric species, MRS2485. These are amphiphilic pyridinium salts that both potently block the Aβ channel and protect neurons from Aβ toxicity. Both block the Aβ channel with similar potency (≈500 nM) and efficacy (100%). However, we find that inhibition by MRS2481 is easily reversible, whereas inhibition by MRS2485 is virtually irreversible. We suggest that both species deserve consideration as candidates for Alzheimer's disease drug discovery. |
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| Keywords: | brain neurodegeneration rational drug design drug toxicity |
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