RESEARCH MONOGRAPH · KDC-MN-055

CX-546

May 9, 2026 Kodiac biolabs Research Revised May 30, 2026 2 min read

Our opinion on this compound

54/100

Improved ampakine with longer activity, useful for sustained AMPA potentiation studies

CX-546 is the second-generation Cortex Pharmaceuticals ampakine that addressed the main limitation of CX-516, namely the brief duration of action. The benzoxazine scaffold replaces the benzoylpyrrolidine, the binding kinetics at the AMPA receptor positive allosteric site are altered to give longer-lasting modulation, and the in vivo pharmacology is correspondingly more sustained.

Mechanistically the compound is interesting because the binding kinetics differ from CX-516 in a way thats relevant for behavioral pharmacology. CX-546 produces deeper inhibition of receptor desensitization at lower concentrations, and the effect on AMPA current waveform is qualitatively different. The Arai and Kessler papers on hippocampal slice physiology document this nicely.

The behavioral signal in animal models tracks with the kinetic improvements. Rodent cognitive paradigms (Morris water maze, novel object recognition, passive avoidance) show consistent enhancement at doses lower than CX-516, and the duration of behavioral effect is correspondingly longer. The Lauterborn and Gall work on BDNF upregulation downstream of sustained AMPA activation is one of the most interesting threads in the literature.

What we like: kinetically cleaner than CX-516, useful for sustained AMPA-PAM studies, and the BDNF upregulation work opens up a really interesting question about whether sustained glutamatergic signaling drives trophic effects in a way thats relevant to neuroprotection research.

What we dont like: human data is essentially nonexistent, the compound never advanced clinically, and the broader pharmacology (off-target activity, metabolic profile) isnt as fully characterized as the receptor work. Safety pharmacology is preclinical at best.

For research, CX-546 is the ampakine we'd reach for if sustained AMPA-PAM activity is the goal and you want a step up in kinetics from CX-516. The BDNF angle makes it worth including in neuroprotection screens, and the binding kinetics make it a useful comparator for the desensitization-blocking class.

Sourcing is more limited than CX-516. Fewer suppliers, more variable QC, and characterization data isnt always available. HPLC verification is essential, and we'd recommend at least one orthogonal method (NMR or mass-spec) for any serious work. Stability is reasonable in dry conditions.

Underused as a research tool, honestly. The pharmacology deserves more attention than its gotten.

Evidence: 35
Mechanism: 70
Reliability: 60
Safety: 55
Sourcing: 50
Value: 50
Signal: 60
Staying power: 50

Plain-language summary Intrigue 42 / 100

CX-546 is a benzoxazine ampakine developed at Cortex as a successor to CX-516 with longer duration. Used in academic research as a higher-potency AMPA potentiator. Not stocked by Kodiac. This monograph is provided for research and educational reference.

Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.

Benzoxazine ampakine

A second-generation Cortex Pharmaceuticals ampakine with improved AMPA receptor modulation kinetics and reduced respiratory depression liability.

Abstract

CX-546 (1-(1,4-benzodioxan-6-ylcarbonyl)piperidine; CAS 215923-54-9; molecular formula C14H17NO3; molecular weight 247.29) is a second-generation Cortex Pharmaceuticals ampakine in the benzoxazine subclass. The compound shows improved AMPA receptor modulation kinetics relative to CX-516, with deeper potentiation per binding event and longer-lasting effect. CX-546 was advanced through preclinical development for cognitive impairment and respiratory disorders (the AMPA potentiation can reverse opioid-induced respiratory depression in animal models). The compound did not advance through pivotal human trials in any indication. Pharmacokinetics: short plasma half-life (2 to 3 hours), oral bioavailability moderate. The compound is sold as a research chemical in jurisdictions where it is not scheduled. Reported research dose ranges in the literature are typically cited as 200 to 500 mg, scaled from rodent studies and unvalidated.

Mechanism of action

AMPA receptor positive allosteric modulator (benzoxazine class). Deeper potentiation than CX-516.

Reported research dose ranges

Reported research dose ranges in the literature span 200 to 500 mg (unvalidated).

References

Lynch G, Rogers G, et al. Pharmacology of CX-546 ampakine class. Cortex Pharmaceuticals development files.
Ren J, et al. Ampakines alleviate respiratory depression in rats. Am J Respir Crit Care Med 2006.

Read the full monograph

The full reference document covers compound identification, discovery and developmental history, mechanism of action, pharmacokinetics, reported research dose ranges, sourcing and quality verification, reconstitution and handling, stack interaction considerations, and a curated reference list. Available as a research-use-only PDF download.

KDC-MN-055

The full reference document is provided strictly for research use only. It reports research dose ranges from the published literature, not instructions for use in humans or animals.

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FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.

Kodiac sells research compounds for investigative use only.

CX-546

Abstract

Mechanism of action

Reported research dose ranges

References

Read the full monograph

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Abstract

Mechanism of action

Reported research dose ranges

References

Read the full monograph

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