Ampakines are a new class of compounds known to enhance attention span and alertness, and facilitate learning and memory. The ampakines take their name from the
glutamatergic AMPA receptorwith which they strongly interact. The AMPA receptor, in turn, gets its name from AMPA, which selectively binds to it.
Ampakines have been investigated by
DARPAfor potential use in increasing military effectiveness.cite web |url=http://www.slate.com/id/2195466/ |title=The U.S. military's sleep-reduction program. - By William Saletan - Slate Magazine |format= |work= |accessdate=2008-07-18]
Unlike earlier stimulants (e.g.
caffeine, methylphenidate(Ritalin), and the amphetamines), ampakines do not seem to have unpleasant, long-lasting side effects such as sleeplessness.
They are currently being investigated as potential treatment for a range of conditions involving mental disability such as
Alzheimer's disease, Parkinson's disease, schizophreniaor neurological disorders as Attention Deficit Hyperactivity Disorder(ADHD), among others. In a 2006study they were shown to have an effect after they had left the body, continuing to enhance learning and memory.
Ampakine activity has been established as one of the modes of action of the well established class of nootropics, the
racetamdrugs such as piracetam, aniracetam, oxiracetamand pramiracetam, however these drugs have multiple modes of action and produce only weak AMPA receptor activation, and it is unclear how significant their ampakine actions are in producing their nootropic effects. 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 CX-717 is currently in Phase II clinical trials as of 2008.
Examples and structure
Four structural classes of ampakine drugs have been developed so far:cite journal |author=O'Neill MJ, Bleakman D, Zimmerman DM, Nisenbaum ES |title=AMPA receptor potentiators for the treatment of CNS disorders |journal=Curr Drug Targets CNS Neurol Disord |volume=3 |issue=3 |pages=181–94 |year=2004 |month=June |pmid=15180479 |doi= |url=]
pyrrolidinederivative racetamdrugs such as piracetamand aniracetam
* the CX- series of drugs which encompass a range of
benzothiazidederivatives such as cyclothiazideand IDRA-21
biarylpropylsulfonamides such as LY-392,098, LY-404,187, LY-451,646and LY-503,430
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, who 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.
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-21and Eli Lilly's LY-503,430have 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.
Their action is theorized to be due to facilitation of transmission at cortical
synapses that use glutamateas neurotransmitter.cite journal |author=Wezenberg E, Verkes RJ, Ruigt GS, Hulstijn W, Sabbe BG |title=Acute effects of the ampakine farampator on memory and information processing in healthy elderly volunteers |journal=Neuropsychopharmacology |volume=32 |issue=6 |pages=1272–83 |year=2007 |month=June |pmid=17119538 |doi=10.1038/sj.npp.1301257 |url=http://dx.doi.org/10.1038/sj.npp.1301257] This in turn may promote plasticityat the synapse, which could translate into better cognitive performance.Fact|date=April 2008
Ampakines work by
allostericallybinding to particular receptors in the brain, called AMPA-type glutamate receptors. This boosts the activity of glutamate, a neurotransmitter, and makes it easier to encode memory and to learn. In addition, some members of the Ampakine family of drugs may also increase levels of trophic factors such as Brain-derived neurotrophic factor( BDNF).
Few side effects have been determined, but an ampakine called farampator (CX-691) has side effects including headache,
somnolence, nausea, and impaired episodic memory. [ [http://www.leaddiscovery.co.uk/Articles/17119538 Acute effects of the ampakine farampator on memory and information processing in healthy elderly volunteers ] ]
It has been proposed as a treatment for
Rett syndrome, after favorable testing in an animal model.cite journal |author=Ogier M, Wang H, Hong E, Wang Q, Greenberg ME, Katz DM |title=Brain-derived neurotrophic factor expression and respiratory function improve after ampakine treatment in a mouse model of Rett syndrome |journal=J. Neurosci. |volume=27 |issue=40 |pages=10912–7 |year=2007 |month=October |pmid=17913925 |doi=10.1523/JNEUROSCI.1869-07.2007 |url=http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=17913925]
*Staubli U, Rogers G, Lynch G. Related Articles, Facilitation of glutamate receptors enhances memory. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):777-81. PMID 8290599
*Staubli U, Perez Y, Xu FB, Rogers G, Ingvar M, Stone-Elander S, Lynch G. Centrally active modulators of glutamate receptors facilitate the induction of long-term potentiation in vivo. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11158-62. PMID 7972026
*Arai A, Lynch G. 1992. Factors regulating the magnitude of long-term potention induced by theta pattern stimulation. Brain Res 598:173-184. PMID 1486479
*Arai A, Silberg J, Kessler M, Lynch G. 1995. Effect of thiocyanate on AMPA receptor mediated responses in excised patches and hippocampal slices. Neuroscience 66:815-827. PMID 7544449
*Suppiramaniam V, Bahr BA, Sinnarajah S, Owens K, Rogers G, Yilma S, Vodyanoy V. 2001. Member of the Ampakine class of memory enhancers prolongs the single channel open time of reconstituted AMPA receptors. Synapse. 40(2):154-8. PMID 11252027
*Porrino LJ, Daunais JB, Rogers GA, Hampson RE, Deadwyler SA (2005) Facilitation of task performance and removal of the effects of sleep deprivation by an ampakine (CX717) in nonhuman primates. PLoS Biol 3(9): e299. PMID 16104830
*Bast T, da Silva BM, Morris RG. Distinct contributions of hippocampal NMDA and AMPA receptors to encoding and retrieval of one-trial place memory. J Neurosci. 2005 Jun 22;25(25):5845-56. PMID 15976073
* [http://www.neurotransmitter.net/ampakines.html Ampakine Article Abstracts]
* [http://www.newscientist.com/article.ns?id=dn7342 Recent Article About CX717]
* [http://www.alzheimersscreen.com/Ampakines.htm Article on Ampakines with reference to Alzheimers]
* [http://www.google.com/patents?id=Qj0pAAAAEBAJ&dq=5650409 US Patent 5,650,409]
* [http://www.google.com/patents?id=d3gEAAAAEBAJ&dq=6030968 US Patent 6,030,968]
* [http://www.google.com/patents?id=83wRAAAAEBAJ&dq=6730677 US Patent 6,730,677]
* [http://www.google.com/patents?id=vRCeAAAAEBAJ&dq=7307073 US Patent 7,307,073]
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