Concept
DISPLAYTITLE:H3 receptor antagonist An H3 receptor antagonist is a classification of drugs used to block the action of histamine at the H3 receptor. 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, betahistine, and pitolisant. The histamine H3 receptor (H3R) 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 (GPCR) in the central nervous system (CNS). 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. 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.