Ampakine
Encyclopedia
Attention span
Attention span is the amount of time that a person can concentrate on a task without becoming distracted. Most educators and psychologists agree that the ability to focus one's attention on a task is crucial for the achievement of one's goals....
and alertness, and facilitate learning
Learning
Learning is acquiring new or modifying existing knowledge, behaviors, skills, values, or preferences and may involve synthesizing different types of information. The ability to learn is possessed by humans, animals and some machines. Progress over time tends to follow learning curves.Human learning...
and memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
. The ampakines take their name from the glutamatergic AMPA receptor
AMPA receptor
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is a non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system . Its name is derived from its ability to be activated by the artificial glutamate analog AMPA...
with which they strongly interact. The AMPA receptor, in turn, gets its name from AMPA
AMPA
AMPA is a compound that is a specific agonist for the AMPA receptor, where it mimics the effects of the neurotransmitter glutamate....
, which selectively binds to it.
Ampakines have been investigated by DARPA for potential use in increasing military effectiveness.
Effects
Unlike earlier stimulants (e.g. caffeineCaffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
, methylphenidate
Methylphenidate
Methylphenidate is a psychostimulant drug approved for treatment of attention-deficit hyperactivity disorder, postural orthostatic tachycardia syndrome and narcolepsy. It may also be prescribed for off-label use in treatment-resistant cases of lethargy, depression, neural insult and obesity...
(Ritalin), and the amphetamine
Amphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
s), 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 and disturbances such as Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
, Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
, schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
, Treatment-resistant depression (TRD) or neurological disorders such 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
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
.
Ampakine activity has been established as one of the modes of action of the well established class of nootropic
Nootropic
Nootropics , also referred to as smart drugs, brain steroids, memory enhancers, cognitive enhancers, and intelligence enhancers, are drugs, supplements, nutraceuticals, and functional foods that improve mental functions such as cognition, memory, intelligence, motivation, attention, and concentration...
s, the racetam
Racetam
Racetams are a class of nootropic drugs that share a pyrrolidone nucleus.-Mechanism:There is no generally accepted mechanism for racetams. They generally show no affinity for the most important receptors, although modulation of most important central neurotransmitters, including acetylcholine and...
drugs such as piracetam
Piracetam
Piracetam is a nootropic drug. Piracetam's chemical name is 2-oxo-1-pyrrolidine acetamide; it shares the same 2-oxo-pyrrolidone base structure with 2-oxo-pyrrolidine carboxylic acid . Piracetam is a cyclic derivative of GABA. It is one of the group of racetams...
, aniracetam
Aniracetam
Aniracetam is an ampakine and nootropic of the racetam chemical class purported to be considerably more potent than piracetam. It is lipid-soluble and has possible cognition-enhancing effects. It has been tested in animals extensively, Alzheimer's patients, and temporarily-impaired healthy subjects...
, oxiracetam
Oxiracetam
Oxiracetam is a nootropic drug of the racetam family.Several animal studies suggest that the substance is safe even when high doses are consumed for a long period of time...
and pramiracetam
Pramiracetam
Pramiracetam is a nootropic dietary supplement derived from piracetam, and is more potent . It belongs to the racetam family of nootropics....
, 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 CX717
CX717
CX717 is an ampakine compound created by Christopher Marrs and Gary Rogers in 1996 at Cortex Pharmaceuticals. It affects the neurotransmitter glutamate, with trials showing the drug improves cognitive functioning and memory.-Approval process:In 2005 the U.S...
is currently in Phase II clinical trials as of 2008.
Examples and structure
Four structural classes of ampakine drugs have been developed so far:- the pyrrolidinePyrrolidinePyrrolidine, also known as tetrahydropyrrole, is an organic compound with the molecular formula C4H9N. It is a cyclic secondary amine with a five-membered heterocycle containing four carbon atoms and one nitrogen atom...
derivative racetamRacetamRacetams are a class of nootropic drugs that share a pyrrolidone nucleus.-Mechanism:There is no generally accepted mechanism for racetams. They generally show no affinity for the most important receptors, although modulation of most important central neurotransmitters, including acetylcholine and...
drugs such as piracetamPiracetamPiracetam is a nootropic drug. Piracetam's chemical name is 2-oxo-1-pyrrolidine acetamide; it shares the same 2-oxo-pyrrolidone base structure with 2-oxo-pyrrolidine carboxylic acid . Piracetam is a cyclic derivative of GABA. It is one of the group of racetams...
and aniracetamAniracetamAniracetam is an ampakine and nootropic of the racetam chemical class purported to be considerably more potent than piracetam. It is lipid-soluble and has possible cognition-enhancing effects. It has been tested in animals extensively, Alzheimer's patients, and temporarily-impaired healthy subjects... - the CX- series of drugs which encompass a range of benzoylpiperidine and benzoylpyrrolidine structures
- benzothiazide derivatives such as cyclothiazideCyclothiazideCyclothiazide is a benzothiadiazide diuretic and antihypertensive that was originally introduced in the United States in 1963 by Eli Lilly and was subsequently also marketed in Europe and Japan...
and IDRA-21IDRA-21IDRA-21 is an ampakine drug derived from aniracetam. IDRA-21 is a chiral molecule, with -IDRA-21 being the active form.IDRA-21 shows nootropic effects in animal studies, significantly improving learning and memory... - biarylpropylsulfonamides such as LY-392,098, LY-404,187LY-404,187LY-404,187 is an ampakine developed by Eli Lilly and Company. It is a member of the biarylpropylsulfonamide class of ampakines....
, LY-451,646 and LY-503,430LY-503,430LY-503,430 is an ampakine drug developed by Eli Lilly.LY-503,430 produces both nootropic and neuroprotective effects, reducing brain damage caused by 6-hydroxydopamine or MPTP and also increasing levels of the neurotrophic factor BDNF in the brain, particularly in the substantia nigra, hippocampus...
Racetam family
The parent compound in which the AMPA modulating activity was first characterised was the well known nootropic drug aniracetamAniracetam
Aniracetam is an ampakine and nootropic of the racetam chemical class purported to be considerably more potent than piracetam. It is lipid-soluble and has possible cognition-enhancing effects. It has been tested in animals extensively, Alzheimer's patients, and temporarily-impaired healthy subjects...
. 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.
Cortex Pharmaceuticals
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 PharmaceuticalsCortex Pharmaceuticals
Cortex Pharmaceuticals is a pharmaceutical company based in Irvine, California specializing in positive allosteric modulators of the AMPA receptor known as Ampakines.-History:February 2005 – Cortex received U.S...
, 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
CX-516
CX-516 is an ampakine and nootropic that acts as an AMPA receptor positive allosteric modulator and is being developed by a collaboration of Cortex and Shire and Servier...
(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.
Eli Lilly/other
Other compounds producing the ampakine activity profile such as IDRA-21IDRA-21
IDRA-21 is an ampakine drug derived from aniracetam. IDRA-21 is a chiral molecule, with -IDRA-21 being the active form.IDRA-21 shows nootropic effects in animal studies, significantly improving learning and memory...
and Eli Lilly's LY-503,430
LY-503,430
LY-503,430 is an ampakine drug developed by Eli Lilly.LY-503,430 produces both nootropic and neuroprotective effects, reducing brain damage caused by 6-hydroxydopamine or MPTP and also increasing levels of the neurotrophic factor BDNF in the brain, particularly in the substantia nigra, hippocampus...
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
Schering-Plough
Schering-Plough Corporation was a United States-based pharmaceutical company. It was founded in 1851 by Ernst Christian Friedrich Schering as Schering AG in Germany. In 1971, the Schering Corporation merged with Plough to form Schering-Plough. On November 4, 2009 Merck & Co...
.
Mechanism
Their action is theorized to be due to facilitation of transmission at cortical synapseSynapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
s that use glutamate as neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
. This in turn may promote plasticity
Synaptic plasticity
In neuroscience, synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathways. Plastic change also results from the alteration of the number of receptors located on a synapse...
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
Brain-derived neurotrophic factor
Brain-derived neurotrophic factor, also known as BDNF, is a protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the "neurotrophin" family of growth factors, which are related to the canonical "Nerve Growth Factor", NGF...
(BDNF).
Side effects
Few side effects have been determined, but an ampakine called farampator (CX-691) has side effects including headache, somnolenceSomnolence
Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
, nausea, and impaired episodic memory
Episodic memory
Episodic memory is the memory of autobiographical events that can be explicitly stated. Semantic and episodic memory together make up the category of declarative memory, which is one of the two major divisions in memory...
.
Uses
It has been proposed as a treatment for Rett syndromeRett syndrome
Rett syndrome is a neurodevelopmental disorder of the grey matter of the brain that almost exclusively affects females. The clinical features include small hands and feet and a deceleration of the rate of head growth . Repetitive hand movements, such as wringing and/or repeatedly putting hands into...
, after favorable testing in an animal model.
Further reading
- 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