AnH3 receptor antagonist is a type ofantihistaminic drug used to block the action ofhistamine atH3 receptors.
Unlike the H1 and H2 receptors which have primarily peripheral actions, but causesedation 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 ofhistamine. Histamine release in the brain triggers secondary release of excitatoryneurotransmitters such asglutamate andacetylcholine via stimulation of H1 receptors in thecerebral cortex. Consequently, unlike the H1 antagonistantihistamines which are sedating, H3 antagonists havestimulant andnootropic effects, and are being researched as potential drugs for the treatment of neurodegenerative conditions such asAlzheimer's disease.
Examples of selective H3 antagonists includeclobenpropit,[1]ABT-239,[2]ciproxifan,[3]conessine,A-349,821,[4]enerisant,[5]betahistine, andpitolisant.[6]
The histamine H3 receptor (H3R) was discovered in 1983 and was one of the last receptors that were discovered using conventionalpharmacological methods.[7] Its structure was discovered later as a part of an effort to identify a commonly expressedG-protein-coupled receptor (GPCR) in thecentral nervous system (CNS).[8] The pharmacology of H3R is very complicated which has made drug development difficult. Many different functionalisoforms 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.[9]
H3Rligands have now been classified asagonists,antagonists orinverse agonists, depending on the signaling assay used.[10][11]
The H3R is a GPCR and it has been described as a presynapticautoreceptor, regulating the release of histamine and also as aheteroreceptor, regulating neurotransmitters such as acetylcholine,dopamine,serotonin,norepinephrine andGABA.[12] The receptor has a high constitutive activity which means that it can signal without being activated by an agonist.[11] H3R regulates the release of neurotransmitters by influencing the amount of intracellularcalcium. When activated, it blocks the influx of calcium which leads to inhibition of the release of neurotransmitters.[8] Antagonists of the receptors cause synthesis and release of these neurotransmitters which promotes waking.[13] H3Rs are mostly expressed on thehistaminergic neurons of the CNS but can also be found in various areas of theperipheral nervous system.[11] The H3R has been found in high densities in thebasal ganglia,hippocampus andcortical areas which are all regions of the brain associated withcognition.[12] The histaminergic system has been described as having a role in thepathophysiology of cognitive symptoms of diseases such as Alzheimer's,schizophrenia andnarcolepsy.[8]
In the beginning of development for H3R ligands the focus was on the agonist histamine which contains animidazole ring in its structure. The structural diversity among H3R is limited and all known H3R agonists today contain an imidazole ring.[11][10] The problem with the imidazole containing compounds was the inhibition ofcytochrome P450isoenzymes which resulted in severe drug interactions.[12][11] They also had difficulty in crossing the blood-brain-barrier. Many compounds were tested but they were too toxic to be useful.[7]
Off target function onH4R 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 fordrug development.[8]
The first imidazole-based antagonist that was developed wasthioperamide which was very potent and selective but was not usable as a drug due tohepatotoxicity. It was originally designed to improve wakefulness and cognition deficit.[7] A recent study showed potential thioperamide treatment of thecircadian rhythm of patients withparkinson's disease.[14]
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 tohERGK+ channel,phospholipidosis as well as problems withP-gp substrate. Strong binding to hERG K+ channel can lead toQT prolongation.[12]
Pitolisant was the first antagonist/inverse agonist to proceed toclinical 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 oralbioavailability and easily accesses the brain. It undergoes extensivefirst-pass effects through theCYP4A4 enzyme in the gut. The wholemetabolic pathway has not yet been established but involves a few CYP enzymes.[15] It has been proved to be useful for maintaining waking-state in the daytime for people with narcolepsy.[7]Side effects encountered in clinical trials were found to be dose-dependent. As expected, some of the adverse effects wereneuropsychiatric in character most common of which wereinsomnia,headache andanxiety. 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.[15]
It can be found under the tradename Wakix and is considered anorphan drug. It was approved by the European Commission on 31 March 2016. It is available in 4.5 mg and 18 mg tablets.[16]
A general structural pattern that is necessary for the antagonist affinity for H3R has been described. An H3R antagonist needs to have a basicamine group which is linked to anaromatic/lipophilic region that is connected to either a polar group or another basic group or a lipophilic region.[8]
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.[17]
Narcolepsy is a sleeping disorder which is characterised by chronic sleepiness.Cataplexy,hypnagogic hallucinations and sleep paralysis can also be present in narcolepsy.[18] H3R antagonism leads to histamine release into thecerebrospinal fluid which promotes wakefulness. Therefore, H3R antagonists have been studied in the hope of treating narcolepsy. Pitolisant has been approved for treatment of narcolepsy[8] and other H3R antagonists are in clinical trials.[9]
Alzheimer's disease is a progressiveneurodegenerative 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.[17]In vivo studies have shown that a number of H3R antagonists facilitate learning and memory.[8] 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 andthalamocortical neurons among others.[17]
ADHD is a neurodevelopmental disorder which is most pronounced in children. Current pharmacological treatments consist of stimulantmedications (e.g. methylphenidate), non-stimulant medication (e.g.atomoxetine) andα2 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.[17]
Inschizophrenia,dopaminergic pathways, among other neurotransmitter systems, play a significant role in the development of the disease.[8][17] 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 inGABAergic 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.[8]