H3 receptor antagonist

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An H3 receptor antagonist is a type of antihistaminic drug used to block the action of histamine at H3 receptors.

Contents

Unlike the H1 and H2 receptors which have primarily peripheral actions, but cause sedation if they are blocked in the brain, H3 receptors are primarily found in the brain and are inhibitory autoreceptors located on histaminergic nerve terminals, which modulate the release of histamine. Histamine release in the brain triggers secondary release of excitatory neurotransmitters such as glutamate and acetylcholine via stimulation of H1 receptors in the cerebral cortex. Consequently, unlike the H1 antagonist antihistamines which are sedating, H3 antagonists have stimulant and nootropic effects, and are being researched as potential drugs for the treatment of neurodegenerative conditions such as Alzheimer's disease.

Examples of selective H3 antagonists include clobenpropit, [1] ABT-239, [2] ciproxifan, [3] conessine, A-349,821, [4] betahistine, and pitolisant. [5]

History

The histamine H3 receptor (H3R) was discovered in 1983 and was one of the last receptors that were discovered using conventional pharmacological methods. [6] Its structure was discovered later as a part of an effort to identify a commonly expressed G-protein-coupled receptor (GPCR) in the central nervous system (CNS). [7] The pharmacology of H3R is very complicated which has made drug development difficult. Many different functional isoforms of the H3R exist which means it could theoretically be possible to target a single isoform specifically. That may, however, be difficult due to genetic variability of the isoforms as well as differing functionality of each one. [8]

H3R ligands have now been classified as agonists, antagonists or inverse agonists, depending on the signaling assay used. [9] [10]

Mechanism of action

The H3R is a GPCR and it has been described as a presynaptic autoreceptor, regulating the release of histamine and also as a heteroreceptor, regulating neurotransmitters such as acetylcholine, dopamine, serotonin, norepinephrine and GABA. [11] The receptor has a high constitutive activity which means that it can signal without being activated by an agonist. [10] H3R regulates the release of neurotransmitters by influencing the amount of intracellular calcium. When activated, it blocks the influx of calcium which leads to inhibition of the release of neurotransmitters. [7] Antagonists of the receptors cause synthesis and release of these neurotransmitters which promotes waking. [12] H3Rs are mostly expressed on the histaminergic neurons of the CNS but can also be found in various areas of the peripheral nervous system. [10] The H3R has been found in high densities in the basal ganglia, hippocampus and cortical areas which are all regions of the brain associated with cognition. [11] The histaminergic system has been described as having a role in the pathophysiology of cognitive symptoms of diseases such as Alzheimer’s, schizophrenia and narcolepsy. [7]

Development

Early pharmacophore

In the beginning of development for H3R ligands the focus was on the agonist histamine which contains an imidazole ring in its structure. The structural diversity among H3R is limited and all known H3R agonists today contain an imidazole ring. [10] [9] The problem with the imidazole containing compounds was the inhibition of cytochrome P450 isoenzymes which resulted in severe drug interactions. [11] [10] They also had difficulty in crossing the blood-brain-barrier. Many compounds were tested but they were too toxic to be useful. [6]

Off target function on H4R and other receptors was also a problem with imidazole-based antagonists. The wide variety of potential pathophysiology of H3R in brain disorders makes H3R antagonists interesting for drug development. [7]

Thioperamide

The first imidazole-based antagonist that was developed was thioperamide which was very potent and selective but was not usable as a drug due to hepatotoxicity. It was originally designed to improve wakefulness and cognition deficit. [6] A recent study showed potential thioperamide treatment of the circadian rhythm of patients with parkinson’s disease. [13]

Chemical structure of thioperamide. Early pharmacophore contained an imidazole ring. Thioperamide-structure.png
Chemical structure of thioperamide. Early pharmacophore contained an imidazole ring.

New pharmacophore

The focus turned to non-imidazole H3R antagonists. They do not seem to interact with the CYP family on the same level as imidazole-based H3R antagonists and can reach the CNS more easily. Unfortunately other problems have come up such as strong binding to hERG K+ channel, phospholipidosis as well as problems with P-gp substrate. Strong binding to hERG K+ channel can lead to QT prolongation. [11]

Pitolisant

Pitolisant was the first antagonist/inverse agonist to proceed to clinical trials and is the only drug that has been approved by regulatory authorities in the US and Europe. It is highly selective for the H3 receptor. Pitolisant has high oral bioavailability and easily accesses the brain. It undergoes extensive first-pass effects through the CYP4A4 enzyme in the gut. The whole metabolic pathway has not yet been established but involves a few CYP enzymes. [14] It has been proved to be useful for maintaining waking-state in the daytime for people with narcolepsy. [6] Side effects encountered in clinical trials were found to be dose-dependent. As expected, some of the adverse effects were neuropsychiatric in character most common of which were insomnia, headache and anxiety. Pitolisant can also potentially cause a prolonged QT interval so caution is advised in cardiac patients. Keeping doses as low as possible can minimize risk for adverse events. [14]

It can be found under the tradename Wakix and is considered an orphan drug. It was approved by the European Commission on 31 March 2016. It is available in 4.5 mg and 18 mg tablets. [15]

Chemical structure of Pitolisant. New pharmacophore contain non-imidazole compounds, in the case of Pitolisant, a piperidine ring. Pitolisant-structure.png
Chemical structure of Pitolisant. New pharmacophore contain non-imidazole compounds, in the case of Pitolisant, a piperidine ring.

Structure activity relationship

A general structural pattern that is necessary for the antagonist affinity for H3R has been described. An H3R antagonist needs to have a basic amine group which is linked to an aromatic/lipophilic region that is connected to either a polar group or another basic group or a lipophilic region. [7]

Structure activity relationship for H3R antagonists H3r sar antagonists.png
Structure activity relationship for H3R antagonists

Clinical significance

H3R antagonists/inverse agonists demonstrate a possible way to treat diseases of the CNS for example Alzheimer's disease (AD), attention deficit hyperactivity syndrome (ADHD), schizophrenia (SCH), pain, and narcolepsy. [16]

Narcolepsy

Narcolepsy is a sleeping disorder which is characterised by chronic sleepiness. Cataplexy, hypnagogic hallucinations and sleep paralysis can also be present in narcolepsy. [17] H3R antagonism leads to histamine release into the cerebrospinal fluid which promotes wakefulness. Therefore, H3R antagonists have been studied in the hope of treating narcolepsy. Pitolisant has been approved for treatment of narcolepsy [7] and other H3R antagonists are in clinical trials. [8]

Alzheimer's disease (AD)

Alzheimer’s disease is a progressive neurodegenerative disease of the brain. Though histamine plays a well documented role in AD, the varying levels of histamine in different areas of the brain make it hard to demonstrate a direct link between histaminergic neurotransmission and pathology of AD. [16] In vivo studies have shown that a number of H3R antagonists facilitate learning and memory. [7] Thioperamide blocks H3R and causes an increase in neuronal histamine release which then modifies cognition processes through H1R and H2R and other receptors (e.g. cholinergic and GABA). Degeneration of histaminergic neurons in AD doesn’t correlate to H3R expressions since a large portion of H3R in the brain are located elsewhere deep in cortical and thalamocortical neurons among others. [16]

Attention deficit hyperactivity disorder (ADHD)

ADHD is a neurodevelopmental disorder which is most pronounced in children. Current pharmacological treatments consist of stimulant medications (e.g. methylphenidate), non-stimulant medication (e.g. atomoxetine) and α2 agonists. These medications can cause adverse effects and some types have the potential to cause addiction. Developing alternative treatments is therefore desirable. In vivo studies show potential of using H3R antagonists in ADHD to aid in attention and cognitive activity by elevating release of neurotransmitters such as acetylcholine and dopamine. [16]

Schizophrenia

In schizophrenia, dopaminergic pathways, among other neurotransmitter systems, play a significant role in the development of the disease. [7] [16] Current treatments are based on first and second generation antipsychotics. These drugs are principally dopamine antagonists, and they can cause many undesirable side-effects. Histaminergic neurons also seem to play a role in schizophrenia, and H3 receptors are co-localized with dopamine receptors in GABAergic neurons. H3 receptor antagonists may be useful in treating the negative and cognitive symptoms of schizophrenia, even if they are not effective in the treatment of its positive symptoms. [7]

See also


Related Research Articles

<span class="mw-page-title-main">Neurotransmitter</span> Chemical substance that enables neurotransmission

A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell.

<span class="mw-page-title-main">Histamine</span> Organic compound involved in immune responses

Histamine is an organic nitrogenous compound involved in local immune responses communication, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered in 1910, it has been considered a local hormone (autocoid) because it lacks the classic endocrine glands to secrete it; however, in recent years, histamine has been recognized as a central neurotransmitter. Histamine is involved in the inflammatory response and has a central role as a mediator of itching. As part of an immune response to foreign pathogens, histamine is produced by basophils and by mast cells found in nearby connective tissues. Histamine increases the permeability of the capillaries to white blood cells and some proteins, to allow them to engage pathogens in the infected tissues. It consists of an imidazole ring attached to an ethylamine chain; under physiological conditions, the amino group of the side-chain is protonated.

<span class="mw-page-title-main">Excitatory synapse</span> Sort of synapse

An excitatory synapse is a synapse in which an action potential in a presynaptic neuron increases the probability of an action potential occurring in a postsynaptic cell. Neurons form networks through which nerve impulses travels, each neuron often making numerous connections with other cells of neurons. These electrical signals may be excitatory or inhibitory, and, if the total of excitatory influences exceeds that of the inhibitory influences, the neuron will generate a new action potential at its axon hillock, thus transmitting the information to yet another cell.

Histamine H<sub>3</sub> receptor Mammalian protein found in Homo sapiens

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.

<span class="mw-page-title-main">Dopaminergic</span> Substance related to dopamine functions

Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate dopamine-related activity. For example, certain proteins such as the dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), and dopamine receptors can be classified as dopaminergic, and neurons that synthesize or contain dopamine and synapses with dopamine receptors in them may also be labeled as dopaminergic. Enzymes that regulate the biosynthesis or metabolism of dopamine such as aromatic L-amino acid decarboxylase or DOPA decarboxylase, monoamine oxidase (MAO), and catechol O-methyl transferase (COMT) may be referred to as dopaminergic as well. Also, any endogenous or exogenous chemical substance that acts to affect dopamine receptors or dopamine release through indirect actions (for example, on neurons that synapse onto neurons that release dopamine or express dopamine receptors) can also be said to have dopaminergic effects, two prominent examples being opioids, which enhance dopamine release indirectly in the reward pathways, and some substituted amphetamines, which enhance dopamine release directly by binding to and inhibiting VMAT2.

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 affects approximately 20% of people who have narcolepsy, and is 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.

Histamine H<sub>1</sub> receptor Histamine receptor

The H1 receptor is a histamine receptor belonging to the family of rhodopsin-like G-protein-coupled receptors. This receptor is activated by the biogenic amine histamine. It is expressed in smooth muscles, on vascular endothelial cells, in the heart, and in the central nervous system. The H1 receptor is linked to an intracellular G-protein (Gq) that activates phospholipase C and the inositol triphosphate (IP3) signalling pathway. Antihistamines, which act on this receptor, are used as anti-allergy drugs. The crystal structure of the receptor has been determined (shown on the right/below) and used to discover new histamine H1 receptor ligands in structure-based virtual screening studies.

<span class="mw-page-title-main">Trace amine</span> Amine receptors in the mammalian brain

Trace amines are an endogenous group of trace amine-associated receptor 1 (TAAR1) agonists – and hence, monoaminergic neuromodulators – that are structurally and metabolically related to classical monoamine neurotransmitters. Compared to the classical monoamines, they are present in trace concentrations. They are distributed heterogeneously throughout the mammalian brain and peripheral nervous tissues and exhibit high rates of metabolism. Although they can be synthesized within parent monoamine neurotransmitter systems, there is evidence that suggests that some of them may comprise their own independent neurotransmitter systems.

<span class="mw-page-title-main">ABT-239</span> Chemical compound

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.

<span class="mw-page-title-main">Thioperamide</span> Chemical compound

Thioperamide is a potent HRH4 antagonist and selective HRH3 antagonist capable of crossing the blood–brain barrier. It was used by Jean-Charles Schwartz in his early experiments regarding the H3 receptor. Thioperamide was found to be an antagonist of histamine autoreceptors, which negatively regulate the release of histamine. The drug enhances the activity of histaminergic neurons by blocking autoreceptors, leading to greater release of histamine.

<span class="mw-page-title-main">Ciproxifan</span> Chemical compound

Ciproxifan is an extremely potent histamine H3 inverse agonist/antagonist.

<span class="mw-page-title-main">Antihistamine</span> Drug that blocks histamine or histamine agonists

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.

<span class="mw-page-title-main">Xanomeline</span> Chemical compound

Xanomeline is a small molecule muscarinic acetylcholine receptor agonist that was first synthesized in a collaboration between Eli Lilly and Novo Nordisk as an investigational therapeutic being studied for the treatment of central nervous system disorders.

<span class="mw-page-title-main">A-349821</span> Chemical compound

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.

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.

Pitolisant, sold under the brand name Wakix among others, is a medication for the treatment of excessive daytime sleepiness in adults with narcolepsy. It is a histamine 3 (H3) receptor antagonist/inverse agonist. It represents the first commercially available medication in its class. Pitolisant enhances the activity of histaminergic neurons in the brain that function to improve a person's wakefulness.

<span class="mw-page-title-main">Pimavanserin</span> Chemical compound

Pimavanserin, sold under the brand name Nuplazid, is an atypical antipsychotic which is approved for the treatment of Parkinson's disease psychosis and is also being studied for the treatment of Alzheimer’s disease psychosis, schizophrenia, agitation, and major depressive disorder. Unlike other antipsychotics, pimavanserin is not a dopamine receptor antagonist.

<span class="mw-page-title-main">Eugeroic</span> Drugs for wakefulness and alertness

Eugeroics, also known as wakefulness-promoting agents and wakefulness-promoting drugs, are a class of drugs that promote wakefulness and alertness. They are medically indicated for the treatment of certain sleep disorders including excessive daytime sleepiness (EDS) in narcolepsy or obstructive sleep apnea (OSA). Eugeroics are also often prescribed off-label for the treatment of EDS in idiopathic hypersomnia. In contrast to classical psychostimulants, such as methylphenidate and amphetamine, which are also used in the treatment of these disorders, eugeroics typically do not produce marked euphoria, and, consequently, have a lower addictive potential.

<span class="mw-page-title-main">Clinical neurochemistry</span>

Clinical neurochemistry is the field of neurological biochemistry which relates biochemical phenomena to clinical symptomatic manifestations in humans. While neurochemistry is mostly associated with the effects of neurotransmitters and similarly functioning chemicals on neurons themselves, clinical neurochemistry relates these phenomena to system-wide symptoms. Clinical neurochemistry is related to neurogenesis, neuromodulation, neuroplasticity, neuroendocrinology, and neuroimmunology in the context of associating neurological findings at both lower and higher level organismal functions.

Jean-Charles Schwartz, born on May 28, 1936, in Paris, is a French neurobiologist, pharmacist and researcher. Husband of Ketty Schwartz, née Gersen (1937-2007) and father of Olivier, Marc and Emmanuelle. He is a member of the Academy of Sciences. He developed pitolisant, the first clinically approved antagonist for H3 receptors.

References

  1. ↑ Yoneyama H, Shimoda A, Araki L, et al. (March 2008). "Efficient approaches to S-alkyl-N-alkylisothioureas: syntheses of histamine H3 antagonist clobenpropit and its analogues". The Journal of Organic Chemistry. 73 (6): 2096–104. doi:10.1021/jo702181x. PMID   18278935.
  2. ↑ Fox GB, Esbenshade TA, Pan JB, Radek RJ, Krueger KM, Yao BB, Browman KE, Buckley MJ, Ballard ME, Komater VA, Miner H, Zhang M, Faghih R, Rueter LE, Bitner RS, Drescher KU, Wetter J, Marsh K, Lemaire M, Porsolt RD, Bennani YL, Sullivan JP, Cowart MD, Decker MW, Hancock AA (April 2005). "Pharmacological properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: II. Neurophysiological characterization and broad preclinical efficacy in cognition and schizophrenia of a potent and selective histamine H3 receptor antagonist". Journal of Pharmacology and Experimental Therapeutics. 313 (1): 176–90. doi:10.1124/jpet.104.078402. ISSN   1521-0103. PMID   15608077. S2CID   15430117.
  3. ↑ Ligneau X, Lin J, Vanni-Mercier G, Jouvet M, Muir JL, Ganellin CR, Stark H, Elz S, Schunack W, Schwartz J (November 1998). "Neurochemical and behavioral effects of ciproxifan, a potent histamine H3-receptor antagonist". The Journal of Pharmacology and Experimental Therapeutics. 287 (2): 658–66. PMID   9808693.
  4. ↑ Esbenshade TA, Fox GB, Krueger KM, Baranowski JL, Miller TR, Kang CH, Denny LI, Witte DG, Yao BB, Pan JB, Faghih R, Bennani YL, Williams M, Hancock AA (1 September 2004). "Pharmacological and behavioral properties of A-349821, a selective and potent human histamine H3 receptor antagonist". Biochemical Pharmacology . 68 (5): 933–45. doi:10.1016/j.bcp.2004.05.048. PMID   15294456.
  5. ↑ Ligneau X, Perrin D, Landais L, Camelin JC, Calmels TP, Berrebi-Bertrand I, Lecomte JM, Parmentier R, Anaclet C, Lin JS, Bertaina-Anglade V, la Rochelle CD, d'Aniello F, Rouleau A, Gbahou F, Arrang JM, Ganellin CR, Stark H, Schunack W, Schwartz JC (January 2007). "BF2.649 [1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride], a nonimidazole inverse agonist/antagonist at the human histamine H3 receptor: Preclinical pharmacology". Journal of Pharmacology and Experimental Therapeutics . 320 (1): 365–75. doi:10.1124/jpet.106.111039. PMID   17005916. S2CID   7489564.
  6. 1 2 3 4 Schwartz, Jean-Charles (2011-06-01). "The histamine H3 receptor: from discovery to clinical trials with pitolisant". British Journal of Pharmacology. 163 (4): 713–721. doi:10.1111/j.1476-5381.2011.01286.x. ISSN   1476-5381. PMC   3111674 . PMID   21615387.
  7. 1 2 3 4 5 6 7 8 9 Sadek, Bassem; Saad, Ali; Sadeq, Adel; Jalal, Fakhreya; Stark, Holger (2016). "Histamine H3 receptor as a potential target for cognitive symptoms in neuropsychiatric diseases". Behavioural Brain Research. 312: 415–430. doi:10.1016/j.bbr.2016.06.051. PMID   27363923. S2CID   40024812.
  8. 1 2 Berlin, Michael; Boyce, Christopher W.; de Lera Ruiz, Manuel (2011-01-13). "Histamine H3 Receptor as a Drug Discovery Target". Journal of Medicinal Chemistry. 54 (1): 26–53. doi:10.1021/jm100064d. ISSN   0022-2623. PMID   21062081.
  9. 1 2 Wijtmans, Maikel; Leurs, Rob; Esch, Iwan de (2007-07-01). "Histamine H3 receptor ligands break ground in a remarkable plethora of therapeutic areas". Expert Opinion on Investigational Drugs. 16 (7): 967–985. doi:10.1517/13543784.16.7.967. ISSN   1354-3784. PMID   17594183. S2CID   21914430.
  10. 1 2 3 4 5 Celanire, Sylvain; Wijtmans, Maikel; Talaga, Patrice; Leurs, Rob; Esch, Iwan J.P. de (2005). "Keynote review: Histamine H3 receptor antagonists reach out for the clinic". Drug Discovery Today. 10 (23–24): 1613–1627. doi:10.1016/s1359-6446(05)03625-1. PMID   16376822.
  11. 1 2 3 4 Gemkow, Mark J.; Davenport, Adam J.; Harich, Silke; Ellenbroek, Bart A.; Cesura, Andrea; Hallett, David (2009). "The histamine H3 receptor as a therapeutic drug target for CNS disorders". Drug Discovery Today. 14 (9–10): 509–515. doi:10.1016/j.drudis.2009.02.011. PMID   19429511.
  12. ↑ Ledneczki, Istvan; Tapolcsányi, Pál; Gábor, Eszter; Éles, János; Greiner, István; Schmidt, Éva; Némethy, Zsolt; Kedves, Rita Soukupné; Balázs, Ottilia (2017). "Discovery of novel steroidal histamine H 3 receptor antagonists/inverse agonists". Bioorganic & Medicinal Chemistry Letters. 27 (19): 4525–4530. doi:10.1016/j.bmcl.2017.08.060. PMID   28888822.
  13. ↑ Masini, D.; Lopes-Aguiar, C.; Bonito-Oliva, A.; Papadia, D.; Andersson, R.; Fisahn, A.; Fisone, G. (2017-04-11). "The histamine H3 receptor antagonist thioperamide rescues circadian rhythm and memory function in experimental parkinsonism". Translational Psychiatry. 7 (4): e1088. doi:10.1038/tp.2017.58. PMC   5416699 . PMID   28398338.
  14. 1 2 Kollb-Sielecka, Marta; Demolis, Pierre; Emmerich, Joseph; Markey, Greg; Salmonson, Tomas; Haas, Manuel (2017). "The European Medicines Agency review of pitolisant for treatment of narcolepsy: summary of the scientific assessment by the Committee for Medicinal Products for Human Use". Sleep Medicine. 33: 125–129. doi:10.1016/j.sleep.2017.01.002. PMID   28449891.
  15. ↑ "European Medicines Agency - Find medicine - Wakix". www.ema.europa.eu. Retrieved 2017-09-27.
  16. 1 2 3 4 5 Vohora, Divya; Bhowmik, Malay (2012). "Histamine H3 receptor antagonists/inverse agonists on cognitive and motor processes: relevance to Alzheimer's disease, ADHD, schizophrenia, and drug abuse". Frontiers in Systems Neuroscience. 6: 72. doi: 10.3389/fnsys.2012.00072 . ISSN   1662-5137. PMC   3478588 . PMID   23109919.
  17. ↑ Scammell, Thomas E. (2015-12-30). "Narcolepsy". New England Journal of Medicine. 373 (27): 2654–2662. doi:10.1056/nejmra1500587. PMID   26716917.
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