title: Small molecule blockers of the Alzheimer Abeta calcium channel potently protect neurons from Abeta cytotoxicity.
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 (Abeta). We have hypothesized that the intrinsic Abeta calcium channel activity of the oligomeric Abeta polymer may be responsible for the neurotoxic properties of Abeta, and that Abeta channel blockers may be candidate AD therapeutics. As a consequence of a rational search paradigm based on the model structure of the Abeta channel, we have identified two compounds of interest: MRS2481 and an enatiomeric species, MRS2485. These are amphiphilic pyridinium salts that both potently block the Abeta channel and protect neurons from Abeta toxicity. Both block the Abeta channel with similar potency (approximately 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.
authors.affiliation: Department of Anatomy, Physiology and Genetics, Uniformed Services University School of Medicine, Bethesda, MD 20814, USA.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Diaz
authors.forename: Olga
authors.initials: O
authors.lastname: Simakova
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: Nelson
authors.initials: N
authors.lastname: Arispe
authors.forename: Harvey B
authors.initials: HB
authors.lastname: Pollard
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D015220:Calcium Channels / Q000737:chemistry / Q000378:metabolism*; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D016716:PC12 Cells; D010666:Phenylpropionates / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D002121:Calcium Channel Blockers; D015220:Calcium Channels; C539502:MRS 2481; C539503:MRS 2485; D018696:Neuroprotective Agents; D010666:Phenylpropionates; D011725:Pyridines