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.

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. 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.

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.