Positive allosteric modulator of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors [1]

Intracortical infusion of CX 717 (CX717; 20 mg/kg) increases the efflux of norepinephrine, dopamine, and serotonin, but not glutamate. CX 717 also produces a rapid (up to 1 hour) increase in brain-derived neurotrophic factor (BDNF) and a more sustained (up to 6 hours) increase in p11 [2]. CX 717 (CX717; 20 mg/kg) has fast (30 minutes) but transient (up to 24 hours) antidepressant-like effects in the forced swim test.

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In well-trained, normal alert rhesus monkeys (Macaca mulatta), intravenous administration of CX717 (0.8 mg/kg) significantly enhanced performance on a cognitive delayed-match-to-sample (DMS) task. Mean overall performance improved from 74.9% correct under vehicle to 90.5% correct under CX717. This enhancement was dose-dependent (tested range 0.3-1.5 mg/kg IV), with maximal effects observed at 1.5 mg/kg. CX717 also markedly reduced response latencies during the task. [1]
In monkeys subjected to 30-36 hours of sleep deprivation, which severely impaired DMS performance (mean correct 62.7%), administration of CX717 (0.8 mg/kg IV) prior to testing completely restored performance to a level significantly above the normal vehicle condition (mean correct 84.5%). This restoration was accompanied by a return of task-related response latencies to shorter durations. [1]
Positron emission tomography (PET) imaging revealed that during the DMS task under normal alert conditions, CX717 administration increased cerebral metabolic rates for glucose (CMRglc) in the prefrontal cortex, dorsal striatum, and medial temporal lobe (including hippocampus) compared to the vehicle condition. Sleep deprivation altered CMRglc patterns in these regions (decreases in prefrontal cortex and dorsal striatum, increases in medial temporal lobe and precuneus). CX717 administration to sleep-deprived animals reversed these altered metabolic patterns, returning CMRglc in most affected brain regions (except the thalamus) towards the pattern seen under normal alert conditions. [1]
Electroencephalogram (EEG) recordings in sleep-deprived monkeys showed increased power in delta (0.5-5 Hz) and beta (18-25 Hz) frequency bands, suggestive of microsleep episodes. Administration of CX717 reduced the power in these frequency bands, shifting the EEG profile towards that observed in the normal alert condition. [1]

Animal/Disease Models: Male SD (SD (Sprague-Dawley)) rats, body weight 280-350 g[2]
Doses: 20 mg/kg (administered as 1 mL/kg)
Route of Administration: intraperitoneal (ip) injection
Experimental Results: Induced antidepressant-like effects (20 mg/kg, ip) does not alter extracellular concentrations of norepinephrine (NA), dopamine (DA), serotonin (5-HT), and glutamate in the medial prefrontal cortex (mPFC).

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Eleven adult male rhesus monkeys (8.0-11.0 kg) were used. They were individually housed under controlled conditions with a 12-hour light/dark cycle. [1]
For behavioral testing, animals performed a visual delayed-match-to-sample (DMS) task daily while seated in a primate chair. They completed 150-300 trials per session. Correct responses were rewarded with diluted fruit juice. Most of their daily fluid requirement was contingent upon task performance to maintain motivation. [1]
For sleep deprivation, animals were kept awake for 30-36 hours continuously in a separate, lit room. Sleep prevention methods included videos, music, occasional treats, gentle cage shaking, and interaction with technicians. [1]
CX717 was dissolved in 10% w/v hydroxypropyl-beta-cyclodextrin and 0.45% saline vehicle. It was administered intravenously via a chronically implanted vascular access port at doses ranging from 0.3 to 1.5 mg/kg (with 0.8 mg/kg being the primary dose reported for key experiments), 10 minutes prior to the start of behavioral testing or PET scan procedures. Vehicle injections were administered prior to non-drug control sessions. [1]
For PET scans measuring cerebral glucose metabolism (CMRglc), animals performed the DMS task for ten trials before receiving an IV injection of [18F]-FDG. They continued performing the task for 40 minutes post-injection during tracer uptake. Subsequently, they were anesthetized and scanned. Blood samples were collected at specified times for tracer concentration measurement. Image analysis was performed using Statistical Parametric Mapping (SPM99) software. [1]

[1]. Facilitation of task performance and removal of the effects of sleep deprivation by an ampakine (CX717) in nonhuman primates. PLoS Biol. 2005 Sep;3(9):e299.

[2]. Antidepressant-Like Effects of CX717, a Positive Allosteric Modulator of AMPA Receptors. Mol Neurobiol. 2020 Aug;57(8):3498-3507.

CX-717 is an ampaciacaine compound that has previously been investigated for the treatment of attention deficit hyperactivity disorder (ADHD) and Alzheimer's disease.

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Drug Indications
It has been investigated for the treatment of attention deficit hyperactivity disorder (ADHD) and Alzheimer's disease.

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Mechanism of Action
CX-717 is an ampaciacaine compound and a positive allosteric modulator of AMPA receptors. Its mechanism of action is thought to be promoting the transmission of neurotransmitters in the cortex that use glutamate as a neurotransmitter. This, in turn, may promote synaptic plasticity, thereby translating into better cognitive function. CX-717 works by allosterically binding to specific receptors in the brain called AMPA-type glutamate receptors. This can enhance the activity of the neurotransmitter glutamate, making memory encoding and learning easier. In addition, CX717 may significantly affect the upregulation of brain-derived neurotrophic factor (BDNF) or nerve growth factor (NGF), both of which are known to stimulate the formation of new circuits in the brain associated with memory and cognitive formation. CX717 is an ampacaine, a class of compounds that act as positive allosteric regulators of AMPA-type glutamate receptors. It is thought to enhance cognitive abilities by modulating glutamatergic synaptic transmission. [1] This study showed that CX717 not only enhances cognitive abilities (short-term/working memory) in non-human primates under normal wakefulness, but also completely reverses severe cognitive impairment caused by 30-36 hours of sleep deprivation, and even restores cognitive abilities to above-normal levels. [1] The cognitive enhancement and sleep deprivation reversal effects are associated with the regulation of brain activity (CMRglc) in key brain regions such as the prefrontal cortex, dorsal striatum, and medial temporal lobe/hippocampus, which are closely related to memory and executive functions. [1]
This study suggests that ampaciacaine-like drugs such as CX717 have the potential to maintain cognitive function under adverse conditions such as sleep deprivation, and their mechanism of action differs from that of traditional psychostimulants. [1]
This study was funded by the Defense Advanced Research Projects Agency (DARPA) and the National Institutes of Health (NIH). Cortex Pharmaceuticals provided the drug CX717. [1]

C11H11N3O3

233.23

233.08

867276-98-0

3323368

White to off-white solid powder

1.4±0.1 g/cm3

422.1±55.0 °C at 760 mmHg

209.1±31.5 °C

0.0±1.0 mmHg at 25°C

1.623

-0.64

0

5

1

17

294

0

KFRQROSRKSVROW-UHFFFAOYSA-N

InChI=1S/C11H11N3O3/c15-11(14-3-5-16-6-4-14)8-1-2-9-10(7-8)13-17-12-9/h1-2,7H,3-6H2

2,1,3-benzoxadiazol-5-yl(morpholin-4-yl)methanone

Ampakine CX-717 Ampakine CX717 Ampakine CX 717 CX 717 CX717 CX-717

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~214.39 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (10.72 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (10.72 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (10.72 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)