H3 receptor antagonist
Examples of selective H3 antagonists include clobenpropit,[1] ABT-239,[2] ciproxifan,[3] conessine, A-349,821,[4] enerisant,[5] betahistine, and pitolisant.
[7] 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).
[11] 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.
[12] 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.
[8] In the beginning of development for H3R ligands the focus was on the agonist histamine which contains an imidazole ring in its structure.
[11][10] The problem with the imidazole containing compounds was the inhibition of cytochrome P450 isoenzymes which resulted in severe drug interactions.
The wide variety of potential pathophysiology of H3R in brain disorders makes H3R antagonists interesting for drug development.
[8] 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.
[7] A recent study showed potential thioperamide treatment of the circadian rhythm of patients with parkinson's disease.
[12] 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.
Pitolisant can also potentially cause a prolonged QT interval so caution is advised in cardiac patients.
[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).
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] In schizophrenia, dopaminergic pathways, among other neurotransmitter systems, play a significant role in the development of the disease.
