Ampakine

Ampakines are a new class of modified benzamide compounds known to enhance attention span and alertness.

The ampakines take their name from the glutamatergic AMPA receptor with which they strongly interact.

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 (2005) 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.

Examples and structure

The parent compound in which the AMPA modulating activity was first discovered was the well known nootropic drug aniracetam. Since then a range of 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. Several other compounds producing the ampakine activity profile such as IDRA-21 and 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 ampakine drugs for human use, in partnership with larger companies such as Schering-Plough.

Mechanism

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

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).

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. ^[1]

References

^ http://www.leaddiscovery.co.uk/Articles/17119538

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

External links

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[1] ttp://www.leaddiscovery.co.uk/Articles/17119538

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