NLX-204

NLX-204
Clinical data
Other namesNLX204
Drug classSerotonin 5-HT1A receptor biased agonist
Identifiers
  • (3-Chloro-4-fluorophenyl)-[4-fluoro-4-[(2-pyridin-2-yloxyethylamino)methyl]piperidin-1-yl]methanone
CAS Number
PubChem CID
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 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. ^ a b Sniecikowska 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.

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