F-15599

F-15,599, also known as NLX-101, is a potent and selective 5-HT_1A receptor full agonist.^[1][2] In addition, it displays functional selectivity, or biased agonism, by preferentially activating postsynaptic serotonin 5-HT_1A receptors over somatodendritic serotonin 5-HT_1A 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]

F-15599

Clinical data
Other names	F-15599; F15599; NLX-101; NLX101
Routes of administration	Oral
Drug class	Serotonin 5-HT1A receptor agonist
Legal status
Legal status	Investigational
Pharmacokinetic data
Metabolism	DB16936DB16936
Identifiers
IUPAC name 3-Chloro-4-fluorophenyl-[4-fluoro-4-[[(5-methylpyrimidin-2-ylmethyl)amino]methyl]piperidin-1-yl]methanone
CAS Number	635323-95-4 Y
PubChem CID	11741361
IUPHAR/BPS	3924
DrugBank	DB16936
ChemSpider	9916065 Y
UNII	83481Y1YCX
ChEMBL	ChEMBL230963
CompTox Dashboard (EPA)	DTXSID901029377
Chemical and physical data
Formula	C19H22ClF2N4O
Molar mass	395.86 g·mol−1
3D model (JSmol)	Interactive image
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
(verify)

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 G_αi G protein subtype over the G_αo subtype.^[3] As a result of its biased agonism for postsynaptic 5-HT_1A 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-HT_1A 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

• Befiradol (F-13,640, NLX-112)
• Eptapirone (F-11,440)