F-15,599 Explained

F-15,599, also known as NLX-101, is a potent and selective 5-HT_1A receptor full agonist.^{[1] [2]} It displays functional selectivity (also known as "biased agonism") by strongly activating 5-HT_1A receptors in the postsynaptic prefrontal cortex while having little effect on somatodendritic autoreceptors in the raphe nucleus. As a result, it has been touted as a preferential postsynaptic 5-HT_1A receptor agonist and has been investigated as a novel potential antidepressant.^{[1] [3]}

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

• Befiradol (F-13,640)
• Eptapirone (F-11,440)

External links

• F-15599 - AdisInsight

Notes and References

1. Maurel JL, Autin JM, Funes P, Newman-Tancredi A, Colpaert F, Vacher B . High-efficacy 5-HT1A agonists for antidepressant treatment: a renewed opportunity . Journal of Medicinal Chemistry . 50 . 20 . 5024–33 . October 2007 . 17803293 . 10.1021/jm070714l.
2. Newman-Tancredi A, Martel JC, Assié MB . Signal transduction and functional selectivity of F15599, a preferential post-synaptic 5-HT1A receptor agonist . British Journal of Pharmacology . 156 . 2 . 338–53 . January 2009 . 19154445 . 2697830 . 10.1111/j.1476-5381.2008.00001.x. etal.
3. Assié MB, Bardin L, Auclair AL . 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 . November 2010 . 20059805 . 10.1017/S1461145709991222. etal. free .
4. Depoortère R, Auclair AL, Bardin L, Colpaert FC, Vacher B, Newman-Tancredi A . 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 . September 2010 . 20488670 . 10.1016/j.euroneuro.2010.04.005. 22222213 .
5. Levitt ES, Hunnicutt BJ, Knopp SJ, Williams JT, Bissonnette JM . A selective 5-HT1a receptor agonist improves respiration in a mouse model of Rett syndrome . Journal of Applied Physiology . 115 . 11 . 1626–33 . December 2013 . 24092697 . 10.1152/japplphysiol.00889.2013 . 3882741.
6. http://neurolixis.com/images/stories/nlx_pf_license_23sept13.pdf{{full citation needed|date=June 2015}}
7. Web site: Enforcement Reports. 2014-03-03. 2015-02-24. https://web.archive.org/web/20150224233953/http://www.accessdata.fda.gov/scripts/opdlisting/oopd/OOPD_Results_2.cfm?Index_Number=410613. dead.
8. Web site: Public Health - European Commission.
9. Web site: April: Rett syndrome research | News and features | University of Bristol.
10. Web site: RSRT Awards $530,000 to Neurolixis for Clinical Development of NLX-101. 24 June 2015.