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NLX-204

From Wikipedia, the free encyclopedia
Robust antidepressant

Pharmaceutical compound
NLX-204
Clinical data
Other namesNLX204
Drug classSerotonin5-HT1A receptorbiased agonist
Identifiers
  • (3-Chloro-4-fluorophenyl)-[4-fluoro-4-[(2-pyridin-2-yloxyethylamino)methyl]piperidin-1-yl]methanone
CAS Number
PubChemCID
ChemSpider
ChEMBL
Chemical and physical data
FormulaC20H22ClF2N3O2
Molar mass409.86 g·mol−1
3D model (JSmol)
  • C1CN(CCC1(CNCCOC2=CC=CC=N2)F)C(=O)C3=CC(=C(C=C3)F)Cl
  • InChI=1S/C20H22ClF2N3O2/c21-16-13-15(4-5-17(16)22)19(27)26-10-6-20(23,7-11-26)14-24-9-12-28-18-3-1-2-8-25-18/h1-5,8,13,24H,6-7,9-12,14H2
  • Key:ZMEGJWWPDKBOER-UHFFFAOYSA-N

NLX-204 is a drug that as of 2026[update] is being evaluated to treatdepression. It is a selectivebiased agonist of the serotonin5-HT1A receptor, distinguished by its preference for activatingERK1/ERK2 phosphorylation pathways.[1][2]

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

Chemistry

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Synthesis

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NLX-204 is synthesized from 3-chloro-4-fluorobenzoic acid. Conversion to the correspondingbenzoyl chloride followed byamidation with4-piperidone yields a benzoylpiperidone intermediate. ADarzens reaction withchloroacetonitrile produces a cyanoepoxide, which undergoes regioselective ring opening with poly(hydrogen fluoride)pyridine to form acyanohydrin. Finalreductive amination with 2-(pyridin-2-yloxy)ethanamine in the presence ofsodium cyanoborohydride affords NLX-204.[1]

See also

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References

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  1. ^abSniecikowska J, Gluch-Lutwin M, Bucki A, Więckowska A, Siwek A, Jastrzebska-Wiesek M, et al. (March 2019). "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.doi:10.1021/acs.jmedchem.9b00062.PMID 30721053.
  2. ^Richin V, Valdebenito M, Bouillot C, Bouvard S, Daligault S, Vidal B, et al. (July 2025). "Multimodal Neuroimaging for the PK/PD Profile of NLX-204: A Biased 5-HT1A Receptor Agonist".ACS Chemical Neuroscience.16 (14):2738–2746.doi:10.1021/acschemneuro.5c00342.PMID 40588541.
  3. ^Papp M, Gruca P, Lason M, Litwa E, Newman-Tancredi A, Depoortère R (November 2023)."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.doi:10.1007/s00213-023-06389-5.PMC 10593613.PMID 37310446.
  4. ^Głuch-Lutwin M, Sałaciak K, Pytka K, Gawalska A, Jamrozik M, Śniecikowska J, et al. (February 2023). "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 114207.doi:10.1016/j.bbr.2022.114207.PMID 36368443.
5-HT1
5-HT1A
5-HT1B
5-HT1D
5-HT1E
5-HT1F
5-HT2
5-HT2A
5-HT2B
5-HT2C
5-HT37
5-HT3
5-HT4
5-HT5A
5-HT6
5-HT7
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