Ampakines or AMPAkines are a subgroup of

AMPA receptor positive allosteric modulator AMPA receptor positive allosteric modulators are positive allosteric modulators (PAMs) of the receptor (AMPR), a type of ionotropic glutamate receptor which mediates most fast synaptic neurotransmission in the central nervous system. Medica ...

s with a

benzamide Benzamide is an organic compound with the chemical formula of C7H7NO. It is the simplest amide derivative of benzoic acid. In powdered form, it appears as a white solid, while in crystalline form, it appears as colourless crystals. It is slightly ...

or closely related

chemical structure A chemical structure of a molecule is a spatial arrangement of its atoms and their chemical bonds. Its determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target m ...

. They are also known as "CX compounds". Ampakines take their name from the

AMPA receptor The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic receptor, ionotropic glutamate receptor (iGluR) and predominantly sodium ion channel that mediates fast excitator ...

(AMPAR), a type of

ionotropic glutamate receptor Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that are activated by the neurotransmitter glutamate. They mediate the majority of excitatory synaptic transmission throughout the central nervous system and are key players in ...

with which the ampakines interact and act as

positive allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimuli. Some of them, like benzodiazepines or alcohol, function as psychoactive drugs. The site that ...

s (PAMs) of. Although all ampakines are AMPAR PAMs, not all AMPAR PAMs are ampakines. 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 (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

treatment-resistant depression Treatment-resistant depression (TRD) is often defined as major depressive disorder in which an affected person does not respond adequately to at least two different antidepressant medications at an adequate dose and for an adequate duration. Inad ...

(TRD) or neurological disorders such as

attention deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple con ...

(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, various ampakines are in clinical trials.

Development

A wide range of ampakines have been developed by RespireRx, which hold patents covering most medical uses of this class of drugs. The best known compounds that have come out of the RespireRx drug development program are CX-516 (Ampalex), CX-546,

CX-614 CX-614 is an ampakine drug developed by Cortex Pharmaceuticals. It has been investigated for its effect on AMPA receptors. Chronic CX-614 treatments produce rapid increases in the synthesis of the brain-derived neurotrophic factor BDNF which ha ...

, CX-691 (farampator), and CX-717. ORG-26576 was developed by RespireRx 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. Presently, CX717 is in phase II clinical trials as a possible non-stimulant pharmacotherapy in the treatment of

ADHD Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple ...

. As the AMPA receptors also mediate respiratory drive, CX717 is also being investigated as a therapy in opioid-induced respiratory depression and spinal-cord injury.

Mechanism of action

Ampakines work by

allosterically In the fields of biochemistry and pharmacology an allosteric regulator (or allosteric modulator) is a substance that binds to a site on an enzyme or receptor distinct from the active site, resulting in a conformational change that alters the p ...

binding to a type of

, called

s. The ampakines are mostly low-impact AMPAR PAMs, though with some exceptions, such as

tulrampator Tulrampator (developmental code names S-47445, CX-1632) is a positive allosteric modulator (PAM) of the AMPA receptor (AMPAR), an ionotropic glutamate receptor, which is under development by RespireRx Pharmaceuticals (formerly Cortex Pharmaceut ...

(S-47445, CX-1632).

Side effects

Few side effects have been determined, but an ampakine called farampator (CX-691) has side effects including headache, drowsiness, nausea, and impaired

episodic memory Episodic memory is the memory of everyday events (such as times, location geography, associated emotions, and other contextual information) that can be explicitly stated or conjured. It is the collection of past personal experiences that occurred ...

Medical applications

An ampakine called CX456 has been proposed as a treatment for

Rett syndrome Rett syndrome (RTT) is a genetic disorder that typically becomes apparent after 6–18 months of age and almost exclusively in girls. Symptoms include impairments in language and coordination, and repetitive movements. Those affected often h ...

, after favorable testing in an animal model. Ampakines have been investigated by

DARPA The Defense Advanced Research Projects Agency (DARPA) is a research and development agency of the United States Department of Defense responsible for the development of emerging technologies for use by the military. Originally known as the Adva ...

to treat

sleep deprivation Sleep deprivation, also known as sleep insufficiency or sleeplessness, is the condition of not having adequate duration and/or quality of sleep to support decent alertness, performance, and health. It can be either Chronic (medicine), chronic ...

-induced cognitive decline.

References

External links

Ampakine Article Abstracts

Recent Article About CX717

US Patent 5,650,409

US Patent 6,030,968

US Patent 6,730,677

US Patent 7,307,073
{{Ionotropic glutamate receptor modulators AMPA receptor positive allosteric modulators