Histamine H3 receptors are expressed in the central nervous system and to a lesser extent the peripheral nervous system, where they act as autoreceptors in presynaptic histaminergic neurons and control histamine turnover by feedback inhibition of histamine synthesis and release. The H3 receptor has also been shown to presynaptically inhibit the release of a number of other neurotransmitters (i.e. it acts as an inhibitory heteroreceptor) including, but probably not limited to dopamine, GABA, acetylcholine, noradrenaline, histamine and serotonin.
The histamine H4 receptor, like the other three histamine receptors, is a member of the G protein-coupled receptor superfamily that in humans is encoded by the HRH4 gene.
The H1 receptor is a histamine receptor belonging to the family of rhodopsin-like G-protein-coupled receptors. This receptor is activated by the biogenic amine histamine. It is expressed in smooth muscles, on vascular endothelial cells, in the heart, and in the central nervous system. The H1 receptor is linked to an intracellular G-protein (Gq) that activates phospholipase C and the inositol triphosphate (IP3) signalling pathway. Antihistamines, which act on this receptor, are used as anti-allergy drugs. The crystal structure of the receptor has been determined (shown on the right/below) and used to discover new histamine H1 receptor ligands in structure-based virtual screening studies.
ABT-239 is an H3-receptor inverse agonist developed by Abbott. It has stimulant and nootropic effects, and has been investigated as a treatment for ADHD, Alzheimer's disease, and schizophrenia. ABT-239 is more active at the human H3 receptor than comparable agents such as thioperamide, ciproxifan, and cipralisant. It was ultimately dropped from human trials after showing the dangerous cardiac side effect of QT prolongation, but is still widely used in animal research into H3 antagonists / inverse agonists.
Thioperamide is a potent HRH4 antagonist and selective HRH3 antagonist capable of crossing the blood–brain barrier. It was used by Jean-Charles Schwartz in his early experiments regarding the H3 receptor. Thioperamide was found to be an antagonist of histamine autoreceptors, which negatively regulate the release of histamine. The drug enhances the activity of histaminergic neurons by blocking autoreceptors, leading to greater release of histamine.
Cipralisant (GT-2331, tentative trade name Perceptin) is an extremely potent histamine H3 receptor ligand originally developed by Gliatech. Cipralisant was initially classified as a selective H3 antagonist, but newer research (2005) suggests also agonist properties, i.e., functional selectivity.
Ciproxifan is an extremely potent histamine H3 inverse agonist/antagonist.
Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic drug that can be bought without a prescription and provides relief from nasal congestion, sneezing, or hives caused by pollen, dust mites, or animal allergy with few side effects. Antihistamines are usually for short-term treatment. Chronic allergies increase the risk of health problems which antihistamines might not treat, including asthma, sinusitis, and lower respiratory tract infection. Consultation of a medical professional is recommended for those who intend to take antihistamines for longer-term use.
Dimaprit is a histamine analog working as a selective H2 histamine receptor agonist.
Dopamine receptor D1, also known as DRD1. It is one of the two types of D1-like receptor family — receptors D1 and D5. It is a protein that in humans is encoded by the DRD1 gene.
An H3 receptor antagonist is a type of antihistaminic drug used to block the action of histamine at H3 receptors.
A-349,821 is a potent and selective histamine H3 receptor antagonist (or possibly an inverse agonist). It has nootropic effects in animal studies, although there do not appear to be any plans for clinical development at present and it is currently only used in laboratory research.
Iodophenpropit is a histamine antagonist which binds selectively to the H3 subtype. Its 125I radiolabelled form has been used for mapping the distribution of H3 receptors in animal studies.
Impentamine is a histamine antagonist selective for the H3 subtype.
Conessine is a steroidal alkaloid found in a number of plant species from the family Apocynaceae, including Holarrhena floribunda, Holarrhena antidysenterica and Funtumia elastica. It acts as a histamine antagonist, selective for the H3 subtype (with an affinity of pKi = 8.27; Ki = ~5 nM). It was also found to have long CNS clearance times, high blood–brain barrier penetration and high affinity for the adrenergic receptors.
VUF-5681 is a potent and selective histamine antagonist which binds selectively to the H3 subtype. However while VUF-5681 blocks the activity of more potent H3 agonists, recent studies suggest that it may have some weak partial agonist activity when administered by itself.
GSK-189,254 is a potent and selective H3 histamine receptor inverse agonist developed by GlaxoSmithKline. It has subnanomolar affinity for the H3 receptor (Ki = 0.2nM) and selectivity of over 10,000x for H3 over other histamine receptor subtypes. Animal studies have shown it to possess not only stimulant and nootropic effects, but also analgesic action suggesting a role for H3 receptors in pain processing in the spinal cord. GSK-189,254 and several other related drugs are currently being investigated as a treatment for Alzheimer's disease and other forms of dementia, as well as possible use in the treatment of conditions such as narcolepsy, or neuropathic pain which do not respond well to conventional analgesic drugs.
SCH-79687 is a histamine antagonist selective for the H3 subtype.
JNJ-5207852 is a histamine antagonist selective for the H3 subtype. It has stimulant and nootropic effects in animal studies, and has been suggested as a possible treatment for some memory defects associated with epilepsy. JNJ-5207852 itself did not progress to clinical development due to poor pharmacokinetic characteristics, but the related compound JNJ-17216498 was in a Phase II clinical trial for the treatment of narcolepsy in 2007.
A-423,579 is one of a range of histamine antagonists developed by Abbott Laboratories which are selective for the H3 subtype, and have stimulant and anorectic effects in animal studies making them potentially useful treatments for obesity. A-423,579 has improved characteristics over earlier drugs in the series with both high efficacy and low toxicity in studies on mice, and is currently in clinical development.
