Aslan2772, The low impact variety of Ampakines (CX-717, CX-691/ORG-24448) have extremely low excitotoxicity potential, even at very high dose (CX-717 hasn't shown any excitotoxicity potential at all). Excitotoxicity has been a problem with the high impact compounds being developed by competing companies however (Cyclothiazide derivatives, Biarylpropylsulfonamides). High and low impacts act at different binding sites on the AMPA receptor. The high impact site appears to be extremely sensitive (particularly to Lilly's Biarylpropylsulfonamides), so these types of compounds haven't had the level of dosing flexibility that would be required of a therapeutic drug. Also, high impacts like Cyclothiazide derivatives tend to act primarily by inhibiting receptor desensitization (which induces excitotoxicity) rather than by inhibiting receptor deactivation (a mechanism which induces less excitotoxicity).
The super-safe low impact compounds like CX-717 improve cognition and memory. The more problematic high impact approach (which strongly upregulates neurotrophin levels) will be needed for indications like Parkinson's, where neuroregeneration is the goal. For the high impact approach, the trick will be to find compounds that can induce excitotoxicity gradually enough, over a sufficiently wide dosing range, to allow for some dosing flexibility.
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