Ampakines, also stylized as AMPAkines, are a subgroup of AMPA receptor positive allosteric modulators with a

benzamide Benzamide is a organic compound with the chemical formula of C6H5C(O)NH2. It is the simplest amide derivative of benzoic acid Benzoic acid is a white (or colorless) solid organic compound with the formula , whose structure consists of a benz ...

or closely related

chemical structure A chemical structure determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target molecule or other solid. Molecular geometry refers to the spatial arrangement of ...

. They are also known as "CX compounds". Ampakines take their name from the AMPA receptor (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 stimulus. Some of them, like benzodiazepines, are drugs. The site that an allosteric modulator binds to ...

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,

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wit ...

treatment-resistant depression Treatment-resistant depression is a term used in psychiatry to describe people with major depressive disorder (MDD) who do not respond adequately to a course of appropriate antidepressant medication within a certain time. Definitions of treatment- ...

(TRD) or neurological disorders such as

attention deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inap ...

(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 RespireRx Pharmaceuticals Inc. (formerly Cortex Pharmaceuticals, Inc.) () is a pharmaceutical company based in Glen Rock, New Jersey specializing in positive allosteric modulators of the AMPA receptor known as Ampakines. History In February 2005 ...

, 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 CX-516 is an ampakine and nootropic that acts as an AMPA receptor positive allosteric modulator and had been undergoing development by a collaboration between Cortex, Shire, and Servier. It was studied as a potential treatment for Alzheimer' ...

(Ampalex),

CX-546 CX-546 is an ampakine drug developed by Cortex Pharmaceuticals. It has been proposed as a treatment for schizophrenia. CX-546 was the second drug of note to come out of the Cortex research program, after CX-516, but while it was an improvement o ...

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 has ...

CX-691 Farampator (developmental code names CX-691, ORG-24448, SCH-900460) is an ampakine drug. It was developed by Cortex Pharmaceuticals, and licensed to Organon BioSciences for commercial development. Following the purchase of Organon by Schering-Pl ...

(farampator), and

CX-717 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 I ...

ORG-26576 ORG-26576 is an ampakine originally developed by Cortex Pharmaceuticals and then licensed to Organon International for development. In animal studies it has been shown to effectively potentiate AMPA receptor function, leading to increased Brain-d ...

was developed by RespireRx but then licensed to Organon for development. Several other compounds such as

CX-701 The Mazda CX-7 is a mid-size crossover SUV from Mazda, and is the production version of the MX-Crossport concept car. It was shown publicly for the first time at the 2006 LA Auto Show in January. Production officially began on February 20, 2006 i ...

CX-1739 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 ...

, 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

. Presently, CX717 is in phase II clinical trials as a possible non-stimulant pharmacotherapy in the treatment of ADHD. 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 biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site. The site to which the effector binds is termed the ''allosteric site ...

binding to a type of

, called AMPA receptors. 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 Farampator (developmental code names CX-691, ORG-24448, SCH-900460) is an ampakine drug. It was developed by Cortex Pharmaceuticals, and licensed to Organon BioSciences for commercial development. Following the purchase of Organon by Schering-P ...

(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 females. 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 Ad ...

for potential use in increasing military effectiveness.

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 Emerging technologies