H3 receptor antagonist
An H3 receptor antagonist is a type of antihistaminic drug used to block the action of histamine at H3 receptors.
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, ABT-239, ciproxifan, conessine, A-349,821, enerisant, betahistine, and pitolisant.
History
The histamine H3 receptor was discovered in 1983 and was one of the last receptors that were discovered using conventional pharmacological methods. Its structure was discovered later as a part of an effort to identify a commonly expressed G-protein-coupled receptor in the central nervous system. 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.H3R ligands have now been classified as agonists, antagonists or inverse agonists, depending on the signaling assay used.
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. The receptor has a high constitutive activity which means that it can signal without being activated by an agonist. 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. Antagonists of the receptors cause synthesis and release of these neurotransmitters which promotes waking. H3Rs are mostly expressed on the histaminergic neurons of the CNS but can also be found in various areas of the peripheral nervous system. 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. 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.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. The problem with the imidazole containing compounds was the inhibition of cytochrome P450 isoenzymes which resulted in severe drug interactions. They also had difficulty in crossing the blood-brain-barrier. Many compounds were tested but they were too toxic to be useful.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.
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. A recent study showed potential thioperamide treatment of the circadian rhythm of patients with parkinson's disease.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.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. It has been proved to be useful for maintaining waking-state in the daytime for people with narcolepsy. 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.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.