F-15,599, also known as NLX-101, is a potent and selective 5-HT_1A receptor

full agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agoni ...

. In addition, it displays

functional selectivity Functional selectivity (or agonist trafficking, biased agonism, biased signaling, ligand bias, and differential engagement) is the ligand-dependent selectivity for certain signal transduction pathways relative to a reference ligand (often the end ...

, or

biased agonism Functional selectivity (or agonist trafficking, biased agonism, biased signaling, ligand bias, and differential engagement) is the ligand-dependent selectivity for certain signal transduction pathways relative to a reference ligand (often the end ...

, by preferentially activating

postsynaptic Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...

serotonin 5-HT_1A receptors over

somatodendritic Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in neuromuscular junction, muscles or glands. Chemical synapses allow neurons to form biological neural ...

serotonin 5-HT_1A

autoreceptor An autoreceptor is a type of Receptor (biochemistry), receptor located in the cell membrane, membranes of neuron, nerve cells. It serves as part of a negative feedback loop in signal transduction. It is only sensitive to the neurotransmitters or ...

s. The drug has been investigated for potential use as a

pharmaceutical drug Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the ...

in the treatment of conditions including depression,

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

cognitive disorder Neurocognitive disorders (NCDs), also known as cognitive disorders (CDs), are a category of mental health disorders that primarily affect cognitive abilities including learning, memory, perception, and problem-solving. Neurocognitive disorders in ...

Rett syndrome Rett syndrome (RTT) is a genetic disorder that typically becomes apparent after 6–18 months of age and almost exclusively in girls. Symptoms include impairments in language and coordination, and repetitive movements. Those affected often h ...

, and

fragile X syndrome Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder. The average IQ in males with FXS is under 55, while affected females tend to be in the borderline to normal range, typically around 70–85. Physical features may include a lo ...

Pharmacology

Pharmacodynamics

In terms of its

, the drug preferentially activates and

phosphorylate In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writt ...

ERK1 Mitogen-activated protein kinase 3, also known as p44MAPK and ERK1, is an enzyme that in humans is encoded by the ''MAPK3'' gene. Function The protein encoded by this gene is a member of the mitogen-activated protein kinase (MAP kinase) fami ...

/ 2 over

receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...

internalization Internalization may refer to: * Internalization (sociology) *Internalization (psychology) ** Internalizing disorder *Internalization (biology) Endocytosis is a cellular process in which substances are brought into the cell. The material to be ...

or inhibition of

adenylyl cyclase Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction: :A ...

. In addition, it preferentially activates the G_αi

G protein G proteins, also known as guanine nucleotide-binding proteins, are a Protein family, family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell (biology), ...

subtype over the G_αo subtype. As a result of its

for

5-HT_1A receptors, F-15,599 shows regional selectivity in its central effects. It mainly activates the

prefrontal cortex In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. It is the association cortex in the frontal lobe. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, ...

cingulate cortex The cingulate cortex is a part of the brain situated in the medial aspect of the cerebral cortex. The cingulate cortex includes the entire cingulate gyrus, which lies immediately above the corpus callosum, and the continuation of this in the cin ...

retrosplenial cortex The retrosplenial cortex (RSC) is a cortical area in the brain comprising Brodmann areas 29 and 30. It is secondary association cortex, making connections with numerous other brain regions. The region's name refers to its anatomical location im ...

septum In biology, a septum (Latin language, Latin for ''something that encloses''; septa) is a wall, dividing a Body cavity, cavity or structure into smaller ones. A cavity or structure divided in this way may be referred to as septate. Examples Hum ...

, and colliculi. Conversely, the drug does not significantly alter

cerebral blood flow Cerebral circulation is the movement of blood through a network of cerebral arteries and veins supplying the brain. The rate of cerebral blood flow in an adult human is typically 750 milliliters per minute, or about 15% of cardiac output. ...

in areas characterized by abundance of

presynaptic In the nervous system, a synapse is a structure that allows a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or a target effector cell. Synapses can be classified as either chemical or electrical, depending o ...

serotonin 5-HT_1A receptors, such as the

raphe nucleus The raphe nuclei (, "seam") are a moderate-size cluster of nuclei found in the brain stem. They have 5-HT1 receptors which are coupled with Gi/Go-protein-inhibiting adenyl cyclase. They function as autoreceptors in the brain and decrease the r ...

. F-15,599 has shown

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

-like,

anxiolytic An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...

-like, antidyskinetic, procognitive, and

antiaggressive A serenic, or anti-aggressive drug, is a type of drug which reduces the capacity for aggression. Examples Serotonergic agents The recreational drug MDMA ("ecstasy") and a variety of related drugs have been described as ''empathogen-entactogens' ...

effects in animals. In

cognitive test Cognitive tests are assessments of the cognitive capabilities of humans and other animals. Tests administered to humans include various forms of IQ tests; those administered to animals include the mirror test (a test of visual self-awareness) and ...

s in rodents, F-15,599 attenuates

memory deficit Amnesia is a deficit in memory caused by brain damage or brain diseases,Gazzaniga, M., Ivry, R., & Mangun, G. (2009) Cognitive Neuroscience: The biology of the mind. New York: W.W. Norton & Company. but it can also be temporarily caused by t ...

s elicited by the

NMDA receptor antagonist NMDA receptor antagonists are a class of drugs that work to receptor antagonist, antagonize, or inhibit the action of, the NMDA, ''N''-Methyl-D-aspartate receptor (NMDA receptor, NMDAR). They are commonly used as anesthetics for humans and anima ...

phencyclidine Phencyclidine or phenylcyclohexyl piperidine (PCP), also known in its use as a street drug as angel dust among other names, is a dissociative anesthetic mainly used recreationally for its significant mind-altering effects. PCP may cause hall ...

(PCP), suggesting that it may improve

cognitive function Cognitive skills are skills of the mind, as opposed to other types of skills such as motor skills, social skills or life skills. Some examples of cognitive skills are literacy, self-reflection, logical reasoning, abstract thinking, critical th ...

in disorders such as

. Another study found that F-15,599 reduces breathing irregularity and

apnea Apnea (also spelled apnoea in British English) is the temporary cessation of breathing. During apnea, there is no movement of the muscles of inhalation, and the volume of the lungs initially remains unchanged. Depending on how blocked the ...

s observed in mice with

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

s of the ''

MeCP2 ''MECP2'' (methyl CpG binding protein 2) is a gene that encodes the protein MECP2. MECP2 appears to be essential for the normal function of nerve cells. The protein seems to be particularly important for mature nerve cells, where it is present in ...

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

, a

mouse model A model organism is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the workings of other organisms. Mod ...

History

F-15,599 was first described in the

scientific literature Scientific literature encompasses a vast body of academic papers that spans various disciplines within the natural and social sciences. It primarily consists of academic papers that present original empirical research and theoretical ...

by 2006.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

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 Neurolixis is a biopharmaceutical company focused on novel drugs for the treatment of human central nervous system diseases. Neurolixis Inc. was founded in 2011 by Mark A. Varney, PhD, and Adrian Newman-Tancredi, PhD, DSc.. The company's therap ...

, a California-based biotechnology company. Neurolixis announced that it intends to re-purpose F-15,599 for the treatment of

.http://neurolixis.com/images/stories/nlx_pf_license_23sept13.pdf and obtained

orphan drug An orphan drug is a medication, pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by th ...

designation from the United States

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) and from the European Commission for this indication. Researchers at the

University of Bristol The University of Bristol is a public university, public research university in Bristol, England. It received its royal charter in 1909, although it can trace its roots to a Merchant Venturers' school founded in 1595 and University College, Br ...

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 trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s for

. Conversely, no recent development has been reported for

depressive disorder A mood disorder, also known as an affective disorder, is any of a group of conditions of mental disorder, mental and Abnormal behavior, behavioral Disorder (medicine), disorder where the main underlying characteristic is a disturbance in the per ...

s or

and development has been discontinued for

cognition disorder Neurocognitive disorders (NCDs), also known as cognitive disorders (CDs), are a category of mental health disorders that primarily affect cognitive abilities including learning, memory, perception, and problem-solving. Neurocognitive disorders incl ...

mood disorder A mood disorder, also known as an affective disorder, is any of a group of conditions of mental and behavioral disorder where the main underlying characteristic is a disturbance in the person's mood. The classification is in the ''Diagnostic ...

s, and

References

{{Serotonin receptor modulators Chlorobenzene derivatives 5-HT1A agonists Secondary amines Benzamides Biased ligands Experimental antidepressants Experimental drugs Experimental drugs developed for schizophrenia Fluoroarenes Piperidines Pyrimidines

Pharmacology

Pharmacodynamics

History

Clinical trials

See also

References