Ampakine

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AMPA

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 receptor with which they strongly interact. The AMPA receptor, in turn, gets its name from AMPA, which selectively binds to it.

Ampakines have been investigated by DARPA for potential use in increasing military effectiveness.^[1]

[edit] Effects

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, schizophrenia or neurological disorders as Attention Deficit Hyperactivity Disorder (ADHD), among others. In a 2006 study 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 racetam drugs such as piracetam, aniracetam, oxiracetam and 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.

[edit] Examples and structure

Four structural classes of ampakine drugs have been developed so far:^[2]

• 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 and LY-503,430

[edit] Racetam family

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.

[edit] Cortex Pharmaceuticals

Cortex Pharmaceutical AMPAkines CX-546, CX-516, and CX-614

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.

[edit] Eli Lilly/other

Other compounds producing the ampakine activity profile such as IDRA-21 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.

[edit] Mechanism

Their action is theorized to be due to facilitation of transmission at cortical synapses that use glutamate as neurotransmitter.^[3] This in turn may promote plasticity at the synapse, which could translate into better cognitive performance.^{[citation needed]}

Ampakines work by allosterically binding 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).

[edit] Side effects

Few side effects have been determined, but an ampakine called farampator (CX-691) has side effects including headache, somnolence, nausea, and impaired episodic memory. ^[4]

[edit] Uses

It has been proposed as a treatment for Rett syndrome, after favorable testing in an animal model.^[5]

[edit] References

1. ^ "The U.S. military's sleep-reduction program. - By William Saletan - Slate Magazine". http://www.slate.com/id/2195466/. Retrieved on 2008-07-18. 
2. ^ O'Neill MJ, Bleakman D, Zimmerman DM, Nisenbaum ES (June 2004). "AMPA receptor potentiators for the treatment of CNS disorders". Curr Drug Targets CNS Neurol Disord 3 (3): 181–94. PMID 15180479. 
3. ^ Wezenberg E, Verkes RJ, Ruigt GS, Hulstijn W, Sabbe BG (June 2007). "Acute effects of the ampakine farampator on memory and information processing in healthy elderly volunteers". Neuropsychopharmacology 32 (6): 1272–83. doi:10.1038/sj.npp.1301257. PMID 17119538. http://dx.doi.org/10.1038/sj.npp.1301257. 
4. ^ Acute effects of the ampakine farampator on memory and information processing in healthy elderly volunteers
5. ^ Ogier M, Wang H, Hong E, Wang Q, Greenberg ME, Katz DM (October 2007). "Brain-derived neurotrophic factor expression and respiratory function improve after ampakine treatment in a mouse model of Rett syndrome". J. Neurosci. 27 (40): 10912–7. doi:10.1523/JNEUROSCI.1869-07.2007. PMID 17913925. 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

[edit] See also

• Nootropic
• CX-516
• Stimulants
• Memory
• AMPA receptor
• Aniracetam

[edit] External links

• Ampakine Article Abstracts
• Recent Article About CX717
• Article on Ampakines with reference to Alzheimers
• US Patent 5,650,409
• US Patent 6,030,968
• US Patent 6,730,677
• US Patent 7,307,073