Small molecule blockers of the Alzheimer Aβ calcium channel potently protect neurons from Aβ cytotoxicity

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 (A beta). We have hypothesized that the intrinsic A beta calcium channel activity of the oligomeric A beta polymer may be responsible for the neurotoxic properties of A beta, and that A beta channel blockers may be candidate AD therapeutics. As a consequence of a rational search paradigm based on the model structure of the A beta channel, we have identified two compounds of interest: MRS2481 and an enatiomeric species, MRS2485. These are amphiphilic pyridinium salts that both potently block the A beta channel and protect neurons from A beta toxicity. Both block the A beta channel with similar potency (similar to 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.