data + articles · 3 listed
newest 2009spec sheet11 rows
CX-614 is a benzoxazine ampakine from the Cortex Pharmaceuticals program and a positive allosteric modulator of AMPA-type glutamate receptors. It is best known as the compound that first demonstrated ampakines can chronically elevate brain-derived neurotrophic factor without permanently down-regulating AMPA receptors, provided dosing is spaced. This made it a foundational tool for the concept of using AMPA modulators to sustain neurotrophin signaling for neuroprotection. It was never a clinical product but remains one of the most cited experimental ampakines.
- Positive allosteric modulation of AMPA receptors
- Chronically raises BDNF when dosed on a spaced schedule
- Enhances TrkB neurotrophin signaling at spine synapses
- Separates the neurotrophic dose from the receptor-down-regulating dose
- Foundational proof of concept for ampakine neuroprotection
- Widely cited and reproducible laboratory tool
- Supports hippocampal excitatory transmission and plasticity
- Continuous saturating exposure down-regulates AMPA-receptor subunits
- Neurotrophin response enters a refractory state without spaced dosing
- Theoretical overexcitation risk outside controlled schedules
- Not validated or available as a consumer substance
Overview
CX-614 is a benzoxazine positive allosteric modulator of AMPA receptors and one of the defining tool compounds of the Cortex ampakine era [3]. Its signal contribution to neuroscience is the demonstration that ampakines can be used to chronically raise brain-derived neurotrophic factor. In cultured hippocampal slices CX-614 rapidly increases BDNF messenger RNA, but continuous exposure produces a refractory state in which the neurotrophin signal fades and AMPA-receptor protein is down-regulated [1].
The key insight was that spaced dosing circumvents this refractory period. Using a 24-hour on, 24-hour off protocol, researchers showed that each application of CX-614 re-induced BDNF messenger RNA and that elevated BDNF protein could be maintained over days [1]. A follow-up study established that BDNF expression is influenced by lower doses and shorter treatments than those that alter AMPA-receptor subunit levels, so daily brief infusions of CX-614 could chronically elevate BDNF and enhance TrkB signaling at spine synapses without changing GluA1 to GluA3 concentrations [2]. This dissociation between neurotrophin induction and receptor down-regulation is the conceptual foundation for using ampakines as neurotrophic agents.
CX-614 was not developed into a medicine, but it is repeatedly cited in reviews of glutamate-based therapeutics as the compound that made the ampakine-neurotrophin strategy credible [3]. It remains a benchmark reagent in studies of AMPA-dependent plasticity and BDNF regulation.
- CX-614 showed that continuously flooding AMPA receptors backfires: BDNF induction enters a refractory state, and only spaced dosing keeps neurotrophin levels high.
- It helped separate the dose needed to raise BDNF from the higher dose that down-regulates AMPA receptors, a distinction central to ampakine drug design.
Mechanism
CX-614 binds the dimer-interface site of the and slows deactivation and desensitization, prolonging excitatory currents. Enhanced -receptor activity drives calcium-dependent and activity-dependent transcription of , increasing neurotrophin protein and downstream receptor signaling at excitatory synapses. Critically, the neurotrophin response is engaged at lower doses and shorter exposures than those that trigger compensatory AMPA-receptor subunit down-regulation, which is why spaced or brief dosing sustains BDNF elevation without blunting the receptor system.
receptor fingerprint
Positive allosteric modulation; slows deactivation and desensitization
expressionInduces neurotrophin transcription, sustainable with spaced dosing
signaling at spine synapsesIncreases neurotrophin receptor activation
-receptor subunit expressionDown-regulates GluA1 to GluA3 with prolonged high exposure
Dosingtypical ranges, not medical advice
interested in protocols and clinical dosages? make an account to see them! ^_^
Safetyrisks and cautions, not medical advice
CX-614 has no human safety data and is characterized only in vitro and in preclinical systems. Continuous high exposure down-regulates AMPA-receptor subunits and induces a neurotrophin refractory state, illustrating that sustained saturating stimulation is counterproductive rather than dangerous per se. As with all high-activity ampakines, theoretical overexcitation is a concern outside a controlled dosing schedule. It is a laboratory reagent without an established tolerability profile in people.
History
CX-614 was developed within the Cortex Pharmaceuticals ampakine portfolio derived from Gary Lynch and colleagues at UC Irvine. During the early 2000s the laboratories of Julie Lauterborn and Christine Gall used it to work out the relationship between ampakine dosing, BDNF induction, and AMPA-receptor regulation, producing a series of influential papers that framed the neurotrophic rationale for the entire drug class.
Reputation
CX-614 enjoys strong standing as a research compound and is routinely cited in the ampakine and neurotrophin literature. It has no consumer profile because it was never marketed and exists only as an experimental tool. Its reputation is that of a pivotal reagent that validated the ampakine-to-BDNF concept.
Subjective profileweighing the evidence above
A laboratory tool, and an important one; it proved BDNF can be raised without permanently down-regulating AMPA receptors, but only on a spaced schedule. There is no human data and no consumer form of it, so what a reader takes away is the dosing lesson, not the molecule.
Resources
This entry is here for reference.
Research
- 2003first citedChronic elevation of brain-derived neurotrophic factor by ampakines
- 2009most recentAmpakines cause sustained increases in brain-derived neurotrophic factor signaling at excitator…
- 1.Chronic elevation of brain-derived neurotrophic factor by ampakines
- 2.Ampakines cause sustained increases in brain-derived neurotrophic factor signaling at excitatory synapses without changes in AMPA receptor subunit expression
- 3.Glutamate-based therapeutic approaches: ampakines
3 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
Why is spaced dosing important for CX-614?
Continuous exposure causes BDNF induction to fade and down-regulates AMPA receptors. A 24-hour on, 24-hour off schedule re-induces BDNF with each dose and sustains elevated neurotrophin protein.
Is CX-614 a drug?
No. It is a Cortex Pharmaceuticals research ampakine that stayed preclinical and was never marketed.
How is CX-614 different from CX-546?
Both are benzoxazine ampakines that raise BDNF, but CX-614 is the compound most associated with defining the spaced-dosing strategy for sustained neurotrophin elevation.
Could CX-614 protect neurons?
It raised the possibility by sustaining BDNF and TrkB signaling, but neuroprotection was a preclinical hypothesis, not a demonstrated clinical outcome.
What does it conceptually pair with?
It is most often studied alongside other ampakines like CX-546; there is no validated human combination.
Limitations of the evidence
- No human safety information
Adverse effects
- Continuous saturating exposure down-regulates AMPA-receptor subunits
- Neurotrophin response enters a refractory state without spaced dosing
- Theoretical overexcitation risk outside controlled schedules
- Not validated or available as a consumer substance