Ampakines are a class of compounds that take their name from the glutamatergic AMPA receptor with which they strongly interact. The AMPA receptor, in turn, gets its name from AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), which selectively binds to it.
They are currently being investigated as potential treatment for a range of conditions involving mental disability and disturbances such as Alzheimer's disease, Parkinson's disease, schizophrenia, treatment-resistant depression (TRD) or neurological disorders such as Attention Deficit Hyperactivity Disorder (ADHD), among others.
More recently developed ampakine compounds are much more potent and selective for the AMPA receptor target, and while none of the newer selective ampakine compounds have yet come onto the market, one compound CX717 is currently in Phase II clinical trials as of 2008.
Examples and structure
Five structural classes of ampakine drugs have been developed so far:
- the pyrrolidine derivative racetam drugs such as piracetam and aniracetam
- the CX- series of drugs which encompass a range of benzoylpiperidine and benzoylpyrrolidine structures
- benzothiazide derivatives such as cyclothiazide and IDRA-21
- biarylpropylsulfonamides such as LY-392,098, LY-404,187, LY-451,646, LY-503,430
- benzylpiperazine derivatives
The parent compound in which the AMPA modulating activity was first characterised was the well known nootropic drug aniracetam. Several drugs in the racetam family have been reported as producing ampakine effects, but while this has been well established for some compounds such as aniracetam and pramiracetam, it is unclear if all of the racetam family act in this way, as the racetam drugs appear to have multiple modes of action.
Since the discovery of the ampakine mode of action as one of the means by which the racetams produce their nootropic effects, a wide range of more selective ampakine drugs have been developed by Cortex Pharmaceuticals, which hold patents covering most medical uses of this class of drugs. The best known compounds that have come out of the Cortex drug development program are CX-516 (Ampalex), CX-546, CX-614, CX-691 (Farampator) and CX-717. Org 26576 was invented by Cortex but then licensed to Organon for development.
Several other compounds such as CX-701, CX-1739, CX-1763 and CX-1837 have also been announced as being under current investigation, and while little information has yet been released about them, CX-1739 is believed to be the most potent compound in this class to date, reportedly some 5x the potency of CX-717.
Other compounds producing the ampakine activity profile such as IDRA-21, S-18986, and Eli Lilly's LY-503,430 have been developed by other pharmaceutical companies, but these are only used in animal research at present, and Cortex is the only company currently developing selective ampakine drugs for human use, in partnership with the larger pharmaceutical company Schering-Plough.
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