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F-15,599

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(Redirected from F-15599) Chemical compound Pharmaceutical compound
F-15,599
Clinical data
Other namesF-15599; F15599; NLX-101; NLX101
Routes of
administration
Oral
Drug classSerotonin 5-HT1A receptor agonist
Legal status
Legal status
  • Investigational
Identifiers
IUPAC name
  • 3-Chloro-4-fluorophenyl-methyl]piperidin-1-yl]methanone
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC19H22ClF2N4O
Molar mass395.86 g·mol
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
  • Key:WAAXKNFGOFTGLP-UHFFFAOYSA-N
  (verify)

F-15,599, also known as NLX-101, is a potent and selective 5-HT1A receptor full agonist. In addition, it displays functional selectivity, or biased agonism, by preferentially activating postsynaptic serotonin 5-HT1A receptors over somatodendritic serotonin 5-HT1A autoreceptors. The drug has been investigated for potential use as a pharmaceutical drug in the treatment of conditions including depression, schizophrenia, cognitive disorders, Rett syndrome, and fragile X syndrome.

Pharmacology

Pharmacodynamics

In terms of its functional selectivity, the drug preferentially activates and phosphorylates ERK1/2 over receptor internalization or inhibition of adenylyl cyclase. In addition, it preferentially activates the Gαi G protein subtype over the Gαo subtype. As a result of its biased agonism for postsynaptic 5-HT1A receptors, F-15,599 shows regional selectivity in its central effects. It mainly activates the prefrontal cortex, cingulate cortex, retrosplenial cortex, septum, and colliculi. Conversely, the drug does not significantly alter cerebral blood flow in areas characterized by abundance of presynaptic serotonin 5-HT1A receptors, such as the raphe nucleus.

F-15,599 has shown antidepressant-like, anxiolytic-like, antidyskinetic, procognitive, and antiaggressive effects in animals. In cognitive tests in rodents, F-15,599 attenuates memory deficits elicited by the NMDA receptor antagonist phencyclidine (PCP), suggesting that it may improve cognitive function in disorders such as schizophrenia. Another study found that F-15,599 reduces breathing irregularity and apneas observed in mice with mutations of the MeCP2 gene, a mouse model of Rett syndrome.

History

F-15,599 was first described in the scientific literature by 2006.

Clinical trials

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. and obtained orphan drug designation from the United States Food and Drug Administration (FDA) and from the European Commission for this indication.

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. In June 2015, the Rett Syndrome Research Trust awarded a grant to Neurolixis to advance F-15599 to clinical development.

As of September 2024, F-15,599 is in phase 1 clinical trials for fragile X syndrome. Conversely, no recent development has been reported for depressive disorders or Rett syndrome and development has been discontinued for cognition disorders, mood disorders, and schizophrenia.

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. ^ Sałaciak K, Pytka K (November 2021). "Biased agonism in drug discovery: Is there a future for biased 5-HT1A receptor agonists in the treatment of neuropsychiatric diseases?". Pharmacol Ther. 227: 107872. doi:10.1016/j.pharmthera.2021.107872. PMID 33905796.
  4. ^ "NLX 101". AdisInsight. 28 September 2024. Retrieved 26 October 2024.
  5. 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): 1285–1298. doi:10.1017/S1461145709991222. PMID 20059805.
  6. 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): 641–654. doi:10.1016/j.euroneuro.2010.04.005. PMID 20488670. S2CID 22222213.
  7. 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.
  8. Assié, M. B., Cosi, C., Slot, L. B., Cussac, D., Martel, J. C., Depoortere, R., ... & Newman-Tancredi, A. (2006, October). Pharmacological profile of F15599, a highly selective serotonin 5-HT1A receptor agonist. In Society for Neuroscience 36th Annual Meeting, Atlanta, Georgia, USA (pp. 14–18). https://scholar.google.com/scholar?cluster=13780243967428028494
  9. http://neurolixis.com/images/stories/nlx_pf_license_23sept13.pdf
  10. "Enforcement Reports". Archived from the original on 2015-02-24. Retrieved 2014-03-03.
  11. "Public Health - European Commission".
  12. "April: Rett syndrome research | News and features | University of Bristol".
  13. "RSRT Awards $530,000 to Neurolixis for Clinical Development of NLX-101". 24 June 2015.


Serotonin receptor modulators
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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