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| Routes of administration | By mouth, IV |
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| Formula | C11H11N3O3 |
| Molar mass | 233.227 g·mol−1 |
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  (what is this?) | |
CX717 is an ampakine compound created by Christopher Marrs and Gary Rogers in 1996 [3] at Cortex Pharmaceuticals. It affects the neurotransmitter glutamate, with trials showing the drug improves cognitive functioning and memory. [4]
In 2005 the U.S. Food and Drug Administration (FDA) accepted Cortex Pharmaceuticals' Investigational New Drug (IND) application to initiate pilot Phase II clinical trials in the United States.
Also, in 2005, the United States Department of Defense funded a study to look into CX717 and the physiological effects of sleepiness. The study found that rhesus monkeys performed faster and better after receiving the drug, and it counteracted the effects of sleep deprivation. [5] [4]
However, a 2006 study funded by DARPA found that CX717 did not improve cognitive performance in humans subjected to simulated night shift work. [6]
In early March 2006 Cortex reported that, in a small pilot Phase II study, CX717 had demonstrated positive clinical and statistical results on the primary endpoint, the ADHD rating scale and the sub-scales related to attention and hyperactivity which are used for the approval of all currently available ADHD treatments. According to a Cortex Pharmaceuticals press release, "Consistent with all previous studies involving over 220 patients and healthy adults, this study demonstrated that CX717 was safe, well tolerated, and produced no increase in heart rate, blood pressure or other cardiovascular side effects".
In April 2007 Cortex Pharmaceuticals submitted two large data packages to the FDA regarding CX717. One data set went to the FDA's Division of Neurology Drug Products for the treatment of Alzheimer's disease, while the other went to the Division of Psychiatry Products where the company filed a second CX717 IND for the treatment of ADHD. According to a Cortex Pharmaceuticals press release, the submitted data package "provides clear evidence that the specific histopathological changes seen in animal toxicology studies, which previously caused the FDA to put CX717 on clinical hold, is a postmortem fixation artifact and is not found in the tissue of the animal when it is still living". [7]
Roger G Stoll PhD, chief executive officer of Cortex, stated,
"When CX717 was removed from clinical hold on October 6, 2006 by the Neurology Division a dose was permitted for continuing a study in patients with Alzheimer's disease, but that dose was too low to permit the assessment of the drug in patients with ADHD. Further information was needed to better understand the cause of the histopathological changes. We now have a substantial data base which clearly documents the fact that the histological changes of concern occur postmortem when the fixative solution is used to prepare the slides of the tissue specimens."
However, in October 2007 the FDA denied Cortex's IND application for a Phase IIb study of CX717 for treatment of ADHD, based on the same animal toxicology results. Cortex responded by inactivating the application, although it will "continue its plans to develop CX717 for the acute treatment of respiratory depression (RD) and continue its study of CX717 in its Alzheimer's disease PET scan study. Cortex believes that the IND application previously filed with the Division of Neurology Products of the FDA for the treatment of Alzheimer's disease will not be affected by the actions of the DPP." [8] The company hopes that after the use of the compound in treating a high-risk acute condition is approved and well-established, the risks of longer-term use at higher doses, such as for treatment of ADHD, will be shown to be less than the FDA had concluded.
The relatively poor oral bioavailability and blood–brain barrier penetration of CX-717 ultimately led to Cortex abandoning development of the 800 mg oral formulation of CX-717 for ADHD, [9] although research into its action in the brain continues. [4] However the unexpected discovery of the strong respiratory stimulant effects of the ampakine drugs on the pre-Botzinger complex of the brain has led to continued development of an intravenous formulation of CX-717 for use alongside opioid analgesics, [10] along with an oral formulation of CX-1739, which is around 3-5× more potent than CX-717 and has better oral bioavailability, and is being trialled for treatment of sleep apnea. [11] Further research has investigated the neurological mechanisms behind the anti-respiratory depressant effects of CX-717, [12] and demonstrated that it can be used in humans alongside opioid drugs to reduce this side effect without affecting analgesia. [13]
Other AMPAkine drugs from Cortex Pharmaceuticals such as CX-546 and CX-614 have already been researched for use in treating Alzheimer's disease and ADHD. These drugs were reasonably effective at reducing the symptoms of Alzheimer's and it was hoped that they could also slow the progression of the disease, but both CX-546 and CX-614 have poor bioavailability, and are only active at very high doses of 1000 mg or more. CX-717 and CX-1739 are newer and more potent drugs in the same series. [14] [15] [16]
Ampakines or AMPAkines are a subgroup of AMPA receptor positive allosteric modulators with a benzamide or closely related chemical structure. They are also known as "CX compounds". Ampakines take their name from the AMPA receptor (AMPAR), a type of ionotropic glutamate receptor with which the ampakines interact and act as positive allosteric modulators (PAMs) of. Although all ampakines are AMPAR PAMs, not all AMPAR PAMs are ampakines.
Dopaminergic means "related to dopamine", a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.
An analeptic, in medicine, is a central nervous system stimulant. The term "analeptic" typically refers to respiratory stimulants. Analeptics are central nervous system (CNS) stimulants that include a wide variety of medications used to treat depression, attention deficit hyperactivity disorder (ADHD), and respiratory depression. Analeptics can also be used as convulsants, with low doses causing patients to experience heightened awareness, restlessness, and rapid breathing. The primary medical use of these drugs is as an anesthetic recovery tool or to treat emergency respiratory depression. Other drugs of this category are prethcamide, pentylenetetrazole, and nikethamide. Nikethamide is now withdrawn due to risk of convulsions. Analeptics have recently been used to better understand the treatment of a barbiturate overdose. Through the use of agents, researchers were able to treat obtundation and respiratory depression.
Guanfacine, sold under the brand name Tenex (immediate-release) and Intuniv (extended-release) among others, is an oral alpha-2a agonist medication used to treat attention deficit hyperactivity disorder (ADHD) and high blood pressure.
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's disease under the brand name Ampalex, and was also being examined as a treatment for ADHD.
Farampator 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-Plough in 2007, the development license to farampator was transferred. The development of farampator was eventually terminated, reportedly due to concerns about cardiac toxicity.
CX-614 is an ampakine drug developed by Cortex Pharmaceuticals. It has been investigated for its effect on AMPA receptors.
CX-546 is an ampakine drug developed by Cortex Pharmaceuticals.
IDRA-21 is a positive allosteric modulator of the AMPA receptor and a benzothiadiazine derivative. It is a chiral molecule, with (+)-IDRA-21 being the active form.
LY-503430 is an AMPA receptor positive allosteric modulator developed by Eli Lilly.
RespireRx Pharmaceuticals Inc. is a pharmaceutical company based in Glen Rock, New Jersey specializing in positive allosteric modulators of the AMPA receptor known as Ampakines.
LY-404187 is an AMPA receptor positive allosteric modulator which was developed by Eli Lilly and Company. It is a member of the biarylpropylsulfonamide class of AMPA receptor potentiators.
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 BDNF release and enhanced neuronal differentiation and survival, as well as producing nootropic effects in standardised assays. Development as an antidepressant has been halted due to a failed Phase II trial for major depressive disorder.
Samidorphan is an opioid antagonist that in the form of olanzapine/samidorphan is used in the treatment of schizophrenia and bipolar disorder. Samidorphan reduces the weight gain associated with olanzapine. Samidorphan is taken by mouth.
Norketamine, or N-desmethylketamine, is the major active metabolite of ketamine, which is formed mainly by CYP3A4. Similarly to ketamine, norketamine acts as a noncompetitive NMDA receptor antagonist, but is about 3–5 times less potent as an anesthetic in comparison.
Pesampator is a positive allosteric modulator (PAM) of the AMPA receptor (AMPAR), an ionotropic glutamate receptor, which was under development by Pfizer for the treatment of cognitive symptoms in schizophrenia. In March 2018, the development of the drug was transferred over from Pfizer to Biogen. It was also under development for the treatment of age-related sensorineural hearing loss, but development for this indication was terminated due to insufficient effectiveness. In July 2022, Biogen discontinued the development of pesampator for cognitive symptoms in schizophrenia due to ineffectiveness.
Mibampator is a positive allosteric modulator (PAM) of the AMPA receptor (AMPAR), an ionotropic glutamate receptor, which was under development by Eli Lilly for the treatment of agitation/aggression in Alzheimer's disease but was never marketed. It reached phase II clinical trials prior to the discontinuation of its development.
Tulrampator is a positive allosteric modulator (PAM) of the AMPA receptor (AMPAR), an ionotropic glutamate receptor, which is under development by RespireRx Pharmaceuticals and Servier for the treatment of major depressive disorder, Alzheimer's disease, dementia, and mild cognitive impairment. Tulrampator was in phase II clinical trial for depression, but failed to show superiority over placebo. There are also phase II clinical trials for Alzheimer's disease and phase I trials for dementia and mild cognitive impairment.
AMPA receptor positive allosteric modulators are positive allosteric modulators (PAMs) of the AMPA receptor (AMPR), a type of ionotropic glutamate receptor which mediates most fast synaptic neurotransmission in the central nervous system.