H3 receptor antagonist
An H3 receptor antagonist is a type of
Unlike the H1 and H2 receptors which have primarily peripheral actions, but cause
Examples of selective H3 antagonists include
History
The histamine H3 receptor (H3R) was discovered in 1983 and was one of the last receptors that were discovered using conventional
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
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]
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]
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]
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
Attention deficit hyperactivity disorder (ADHD)
ADHD is a neurodevelopmental disorder which is most pronounced in children. Current pharmacological treatments consist of stimulant
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
- H1-receptor antagonist
- H2-receptor antagonist
References
- PMID 18278935.
- S2CID 15430117.
- from the original on 2020-05-02. Retrieved 2013-12-18.
- PMID 15294456.
- S2CID 7489564.
- ^ PMID 21615387.
- ^ S2CID 40024812.
- ^ PMID 21062081.
- ^ S2CID 21914430.
- ^ PMID 16376822.
- ^ PMID 19429511.
- PMID 28888822.
- PMID 28398338.
- ^ PMID 28449891.
- ^ "European Medicines Agency - Find medicine - Wakix". www.ema.europa.eu. Archived from the original on 2017-09-27. Retrieved 2017-09-27.
- ^ PMID 23109919.
- PMID 26716917.