F-15,599

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
  • 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
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC19H22ClF2N4O
Molar mass395.86 g·mol−1
3D model (JSmol)
  • Cc3cnc(nc3)CNCC(F)(CC2)CCN2C(=O)c(cc1Cl)ccc1F
  • 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
  (verify)

F-15,599, also known as NLX-101, is a potent and selective 5-HT1A receptor full agonist.[1][2] In addition, it displays functional selectivity, or biased agonism, by preferentially activating postsynaptic serotonin 5-HT1A receptors over somatodendritic serotonin 5-HT1A autoreceptors.[3][1][2] 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.[4]

Pharmacology

Pharmacodynamics

In terms of its functional selectivity, the drug preferentially activates and phosphorylates ERK1/2 over receptor internalization or inhibition of adenylyl cyclase.[3] In addition, it preferentially activates the Gαi G protein subtype over the Gαo subtype.[3] As a result of its biased agonism for postsynaptic 5-HT1A receptors, F-15,599 shows regional selectivity in its central effects.[3] It mainly activates the prefrontal cortex, cingulate cortex, retrosplenial cortex, septum, and colliculi.[3] 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.[3][1][2]

F-15,599 has shown antidepressant-like, anxiolytic-like, antidyskinetic, procognitive, and antiaggressive effects in animals.[3][1][2][5] 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.[6] 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.[3][7]

History

F-15,599 was first described in the scientific literature by 2006.[8]

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.[9] and obtained orphan drug designation from the United States Food and Drug Administration (FDA)[10] and from the European Commission for this indication.[11]

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.[12] In June 2015, the Rett Syndrome Research Trust awarded a grant to Neurolixis to advance F-15599 to clinical development.[13]

As of September 2024, F-15,599 is in phase 1 clinical trials for fragile X syndrome.[4] 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.[4]

See also

References

  1. ^ a b c d 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. ^ a b c d 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. ^ a b c d e f g h 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. ^ a b c "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[full citation needed]
  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.