F-15,599

F-15,599, also known as NLX-101, is a potent and selective 5-HT1A receptor full agonist.[1][2] It displays functional selectivity (also known as "biased agonism") by strongly activating 5-HT1A receptors in the postsynaptic prefrontal cortex while having little effect on somatodendritic autoreceptors in the raphe nucleus.[1][2] As a result, it has been touted as a preferential postsynaptic 5-HT1A receptor agonist and has been investigated as a novel potential antidepressant.[1][2][3]

F-15,599
Clinical data
Routes of
administration		Oral
Legal status
Legal status
  • Investigational
Identifiers
IUPAC name
  • 3-Chloro-4-fluorophenyl-[4-fluoro-4-[[(5-methylpyrimidin-2-ylmethyl)amino]methyl]piperidin-1-yl]methanone
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
Chemical and physical data
FormulaC19H22ClF2N4O
Molar mass395.86 g·mol−1
3D model (JSmol)
SMILES
  • Cc3cnc(nc3)CNCC(F)(CC2)CCN2C(=O)c(cc1Cl)ccc1F
InChI
  • InChI=1S/C19H21ClF2N4O/c1-13-9-24-17(25-10-13)11-23-12-19(22)4-6-26(7-5-19)18(27)14-2-3-16(21)15(20)8-14/h2-3,8-10,23H,4-7,11-12H2,1H3 N
  • Key:WAAXKNFGOFTGLP-UHFFFAOYSA-N N
 NY (what is this?)  (verify)

In cognitive tests in rodent, F-15,599 attenuates memory deficits elicited by the NMDA receptor antagonist PCP, suggesting that it may improve cognitive function in disorders such as schizophrenia.[4]

A subsequent study showed that F-15,599 reduces breathing irregularity and apneas observed in mice with mutations of the MeCP2 gene.[5] Dysruption of MeCP2 gene expression underlies Rett syndrome, a debilitating neurodevelopmental orphan disease.

F-15,599 was discovered and initially developed by Pierre Fabre Médicament, a French pharmaceuticals company. In September 2013, F-15,599 was out-licensed to Neurolixis, a California-based biotechnology company. Neurolixis announced that it intends to re-purpose F-15,599 for the treatment of Rett syndrome.[6] and obtained Orphan Drug designation from the United States Food and Drug Administration (FDA)[7] and from the European Commission for this indication.[8]

Researchers at the University of Bristol are investigating the activity of F-15599 in animal models of Rett Syndrome, with support from the International Rett Syndrome Foundation.[9] In June 2015, the Rett Syndrome Research Trust awarded a grant to Neurolixis to advance F-15599 to clinical development.[10]

See also

References
  1. Maurel JL, Autin JM, Funes P, Newman-Tancredi A, Colpaert F, Vacher B (October 2007). "High-efficacy 5-HT1A agonists for antidepressant treatment: a renewed opportunity". Journal of Medicinal Chemistry. 50 (20): 5024–33. doi:10.1021/jm070714l. PMID 17803293.
  2. Newman-Tancredi A, Martel JC, Assié MB, et al. (January 2009). "Signal transduction and functional selectivity of F15599, a preferential post-synaptic 5-HT1A receptor agonist". British Journal of Pharmacology. 156 (2): 338–53. doi:10.1111/j.1476-5381.2008.00001.x. PMC 2697830. PMID 19154445.
  3. Assié MB, Bardin L, Auclair AL, et al. (November 2010). "F15599, a highly selective post-synaptic 5-HT(1A) receptor agonist: in-vivo profile in behavioural models of antidepressant and serotonergic activity". The International Journal of Neuropsychopharmacology. 13 (10): 1285–98. doi:10.1017/S1461145709991222. PMID 20059805.
  4. Depoortère R, Auclair AL, Bardin L, Colpaert FC, Vacher B, Newman-Tancredi A (September 2010). "F15599, a preferential post-synaptic 5-HT1A receptor agonist: activity in models of cognition in comparison with reference 5-HT1A receptor agonists". European Neuropsychopharmacology. 20 (9): 641–54. doi:10.1016/j.euroneuro.2010.04.005. PMID 20488670. S2CID 22222213.
  5. Levitt ES, Hunnicutt BJ, Knopp SJ, Williams JT, Bissonnette JM (December 2013). "A selective 5-HT1a receptor agonist improves respiration in a mouse model of Rett syndrome". Journal of Applied Physiology. 115 (11): 1626–33. doi:10.1152/japplphysiol.00889.2013. PMC 3882741. PMID 24092697.
  6. http://neurolixis.com/images/stories/nlx_pf_license_23sept13.pdf%5B%5D
  7. "Enforcement Reports".
  8. "Public Health - European Commission".
  9. "April: Rett syndrome research | News and features | University of Bristol".
  10. "RSRT Awards $530,000 to Neurolixis for Clinical Development of NLX-101". 24 June 2015.
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