Hydroxyzine, sold under the brand names Atarax and Vistaril among others, is an antihistamine medication. It is used in the treatment of itchiness, anxiety, insomnia, and nausea. It is used either by mouth or injection into a muscle.
Histamine H3 receptors are expressed in the central nervous system and to a lesser extent the peripheral nervous system, where they act as autoreceptors in presynaptic histaminergic neurons and control histamine turnover by feedback inhibition of histamine synthesis and release. The H3 receptor has also been shown to presynaptically inhibit the release of a number of other neurotransmitters (i.e. it acts as an inhibitory heteroreceptor) including, but probably not limited to dopamine, GABA, acetylcholine, noradrenaline, histamine and serotonin.
Cataplexy is a sudden and transient episode of muscle weakness accompanied by full conscious awareness, typically triggered by emotions such as laughing, crying, or terror. Cataplexy is the first symptom to appear in about 10% of cases of narcolepsy, caused by an autoimmune destruction of hypothalamic neurons that produce the neuropeptide hypocretin, which regulates arousal and has a role in stabilization of the transition between wake and sleep states. Cataplexy without narcolepsy is rare and the cause is unknown.
ABT-239 is an H3-receptor inverse agonist developed by Abbott. It has stimulant and nootropic effects, and has been investigated as a treatment for ADHD, Alzheimer's disease, and schizophrenia. ABT-239 is more active at the human H3 receptor than comparable agents such as thioperamide, ciproxifan, and cipralisant. It was ultimately dropped from human trials after showing the dangerous cardiac side effect of QT prolongation, but is still widely used in animal research into H3 antagonists / inverse agonists.
Ciproxifan is an extremely potent histamine H3 inverse agonist/antagonist.
Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic drug that can be bought without a prescription and provides relief from nasal congestion, sneezing, or hives caused by pollen, dust mites, or animal allergy with few side effects. Antihistamines are usually for short-term treatment. Chronic allergies increase the risk of health problems which antihistamines might not treat, including asthma, sinusitis, and lower respiratory tract infection. Consultation of a medical professional is recommended for those who intend to take antihistamines for longer-term use.
Dopamine receptor D1, also known as DRD1. It is one of the two types of D1-like receptor family — receptors D1 and D5. It is a protein that in humans is encoded by the DRD1 gene.
An H3 receptor antagonist is a type of antihistaminic drug used to block the action of histamine at H3 receptors.
A-349,821 is a potent and selective histamine H3 receptor antagonist (or possibly an inverse agonist). It has nootropic effects in animal studies, although there do not appear to be any plans for clinical development at present and it is currently only used in laboratory research.
VUF-5681 is a potent and selective histamine antagonist which binds selectively to the H3 subtype. However while VUF-5681 blocks the activity of more potent H3 agonists, recent studies suggest that it may have some weak partial agonist activity when administered by itself.
Narcolepsy is a chronic neurological disorder that impairs the ability to regulate sleep–wake cycles, and specifically impacts REM sleep. The pentad symptoms of narcolepsy include excessive daytime sleepiness (EDS), sleep-related hallucinations, sleep paralysis, disturbed nocturnal sleep (DNS), and cataplexy. People with narcolepsy tend to sleep about the same number of hours per day as people without it, but the quality of sleep is typically compromised.
GSK-189,254 is a potent and selective H3 histamine receptor inverse agonist developed by GlaxoSmithKline. It has subnanomolar affinity for the H3 receptor (Ki = 0.2nM) and selectivity of over 10,000x for H3 over other histamine receptor subtypes. Animal studies have shown it to possess not only stimulant and nootropic effects, but also analgesic action suggesting a role for H3 receptors in pain processing in the spinal cord. GSK-189,254 and several other related drugs are currently being investigated as a treatment for Alzheimer's disease and other forms of dementia, as well as possible use in the treatment of conditions such as narcolepsy, or neuropathic pain which do not respond well to conventional analgesic drugs.
JNJ-5207852 is a histamine antagonist selective for the H3 subtype. It has stimulant and nootropic effects in animal studies, and has been suggested as a possible treatment for some memory defects associated with epilepsy. JNJ-5207852 itself did not progress to clinical development due to poor pharmacokinetic characteristics, but the related compound JNJ-17216498 was in a Phase II clinical trial for the treatment of narcolepsy in 2007.
Pitolisant, sold under the brand name Wakix among others, is a medication used for the treatment of excessive daytime sleepiness in adults with narcolepsy. It is an inverse agonist of the histamine H3 receptor. It represents the first commercially available medication in its class, so that the U.S. Food and Drug Administration (FDA) declares it a first-in-class medication. Pitolisant enhances the activity of histaminergic neurons in the brain that function to improve a person's wakefulness. It was approved by the European Medicines Agency (EMA) in March 2016 for narcolepsy with or without cataplexy, and for excessive daytime sleepiness by the FDA in August 2019. The most common side effects include difficulty sleeping, nausea, and feeling worried.
Idiopathic hypersomnia (IH) is a neurological disorder which is characterized primarily by excessive sleep and excessive daytime sleepiness (EDS). Idiopathic hypersomnia was first described by Bedrich Roth in 1976, and it can be divided into two forms: polysymptomatic and monosymptomatic. The condition typically becomes evident in early adulthood and most patients diagnosed with IH will have had the disorder for many years prior to their diagnosis. As of August 2021, an FDA-approved medication exists for IH called Xywav, which is an oral solution of calcium, magnesium, potassium, and sodium oxybates; in addition to several off-label treatments.
A wakefulness-promoting agent (WPA), or wake-promoting agent, is a drug that increases wakefulness and arousal. They are similar to but distinct from psychostimulants, which not only promote wakefulness but also produce other more overt central nervous system effects, such as improved mood, energy, and motivation. Wakefulness-promoting agents are used to treat narcolepsy and hypersomnia as well as to promote wakefulness and increase performance in healthy people.
Suvorexant, sold under the brand name Belsomra, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or maintenance in adults. Suvorexant helps with falling asleep faster, sleeping longer, being awake less in the middle of the night, and having better quality of sleep. Its effectiveness is modest, and is similar to that of other orexin antagonists, but is lower than that of benzodiazepines and Z-drugs. Suvorexant is taken by mouth.
EPPTB, also known as RO5212773 or RO-5212773, is a drug developed by Hoffmann-La Roche which acts as a potent and selective antagonist or inverse agonist of the trace amine-associated receptor 1 (TAAR1). The drug was the first selective antagonist developed for the TAAR1. It is a potent agonist of the mouse and rat TAAR1, but is dramatically less potent as an agonist of the human TAAR1. EPPTB has been used in scientific research to demonstrate an important role for TAAR1 in regulation of dopaminergic signaling in the limbic system.
Flmodafinil, also known as bisfluoromodafinil and lauflumide, is a wakefulness-promoting agent related to modafinil which has been developed for treatment of a variety of different medical conditions. These include chronic fatigue syndrome, idiopathic hypersomnia, narcolepsy, attention deficit hyperactivity disorder (ADHD), and Alzheimer's disease. Aside its development as a potential pharmaceutical drug, flmodafinil is sold online and used non-medically as a nootropic.
Samelisant (INNTooltip International Nonproprietary Name; developmental code name SUVN-G3031) is an experimental wakefulness-promoting agent acting as a selective histamine H3 receptor inverse agonist which is under development for the treatment of narcolepsy. It was also under development for the treatment of cognition disorders and Parkinson's disease, but no recent development has been reported for these indications. As of June 2024, samelisant is in phase 2 clinical trials for the treatment of narcolepsy.
