Chemistry:NLX-204

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NLX-204 is a drug that as of 2026 is being evaluated to treat depression. It is a selective biased agonist of the serotonin 5-HT1A receptor, distinguished by its preference for activating ERK1/ERK2 phosphorylation pathways.[1][2]

This compound has demonstrated potent and rapid-acting antidepressant-like effects in preclinical models, with activity comparable to ketamine in reversing symptoms of depression and treatment-resistant depression in rodents. Recent studies suggest that NLX-204 also offers potential benefits reversing memory deficits and anxiety, positioning it as a candidate for a rapid-acting antidepressant therapy.[3][4]

Chemistry

Synthesis

NLX-204 is synthesized from 3-chloro-4-fluorobenzoic acid. Conversion to the corresponding benzoyl chloride followed by amidation with 4-piperidone yields a benzoylpiperidone intermediate. A Darzens reaction with chloroacetonitrile produces a cyanoepoxide, which undergoes regioselective ring opening with poly(hydrogen fluoride)pyridine to form a cyanohydrin. Final reductive amination with 2-(pyridin-2-yloxy)ethanamine in the presence of sodium cyanoborohydride affords NLX-204.[1]

See also

References

  1. ↑ 1.0 1.1 "Novel Aryloxyethyl Derivatives of 1-(1-Benzoylpiperidin-4-yl)methanamine as the Extracellular Regulated Kinases 1/2 (ERK1/2) Phosphorylation-Preferring Serotonin 5-HT1A Receptor-Biased Agonists with Robust Antidepressant-like Activity". Journal of Medicinal Chemistry 62 (5): 2750–2771. March 2019. doi:10.1021/acs.jmedchem.9b00062. PMID 30721053. 
  2. ↑ "Multimodal Neuroimaging for the PK/PD Profile of NLX-204: A Biased 5-HT1A Receptor Agonist". ACS Chemical Neuroscience 16 (14): 2738–2746. July 2025. doi:10.1021/acschemneuro.5c00342. PMID 40588541. 
  3. ↑ "The 5-HT1A receptor biased agonists, NLX-204 and NLX-101, display ketamine-like RAAD and anti-TRD activities in rat CMS models". Psychopharmacology 240 (11): 2419–2433. November 2023. doi:10.1007/s00213-023-06389-5. PMID 37310446. 
  4. ↑ "The 5-HT1A receptor biased agonist, NLX-204, shows rapid-acting antidepressant-like properties and neurochemical changes in two mouse models of depression". Behavioural Brain Research 438. February 2023. doi:10.1016/j.bbr.2022.114207. PMID 36368443. 



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