2. H3 RECEPTOR
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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.
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3. CONTD..
The gene sequence for H3 receptors expresses only about 22% and 20%
homology with both H1 and H2 receptors respectively.
There is much interest in the histamine H3 receptor as a potential therapeutic
target because of its involvement in the neuronal mechanism behind many
cognitive disorders and especially its location in the central nervous system.
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4. Function
Like all histamine receptors, the H3 receptor is a G-protein coupled receptor. The
H3 receptor is coupled to the Gi G-protein, so it leads to inhibition of the
formation of cAMP. Also, the β and γ subunits interact with N-type voltage gated
calcium channels, to reduce action potential mediated influx of calcium and hence
reduce neurotransmitter release. H3 receptors function as presynaptic
autoreceptors on histamine-containing neurons
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5. CONTD…
The diverse expression of H3 receptors throughout the cortex and
subcortex indicates its ability to modulate the release of a large
number of neurotransmitters.
H3 receptors are thought to play a part in the control of satiety
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6. Isoforms
There are at least six H3 receptor isoforms in the human, and more than 20 discovered so
far. In rats there have been six H3receptor subtypes identified so far. Mice also have three
reported isoforms. These subtypes all have subtle difference in their pharmacology (and
presumably distribution, based on studies in rats) but the exact physiological role of these
isoforms is still unclear.
ISOFORMS
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7. Pharmacology
Agonists
There are currently no therapeutic products acting as selective agonists for H3 receptors,
although there are several compounds used as research tools which are reasonably selective
agonists. Some examples are:
alpha-Methylhistamine
Immipip
Cipralisant
PHARMACOLOGY
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8. ALPHA METHYL
HISTAMINE
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α-Methylhistamine is a histamine
agonist selective for the receptor
subtype H₃. It causes lowering of blood
pressure and a decrease of heart rate
in animal models
Chemical Formula C6H11N3
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Cipralisant is an extremely potent
histamine H₃ receptor ligand originally
developed by Gliatech. Cipralisant was
initially classified as a selective H₃
antagonist, but newer research
suggests also agonist properties, i. e.
functional selectivity
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CIPRALISANT
12. Ciproxifan
Ciproxifan is an extremely potent histamine H3 inverse agonist/antagonist. The
histamine H3 receptor is an inhibitory autoreceptor located on histaminergic nerve
terminals, and is believed to be involved in modulating the release of histamine in
the brain.
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13. Clobenpropit
Clobenpropit is a histamine H₃ receptor antagonist. It has neuroprotective effects
via stimulation of GABA release in brain cells in vitro
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14. Conessine
Conessine is a steroid alkaloid found in a number of plant species from the family
Apocynaceae. It is a H3 receptor drug.
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15. Therapeutic potential
The H3-receptor is a promising potential therapeutical target for many (cognitive)
disorders, because it is linked to the central nervous system and its regulation of other
neurotransmitters. Examples of such disorders are: sleep disorders (including narcolepsy),
Tourette syndrome, Parkinson, OCD, ADHD, and drug addictions.
This receptor has been proposed as a target for treating sleep disorders. The receptor has
also been proposed as a target for treating neuropathic pain.
THERAPEUTIC POTENTIAL
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16. CONTD…
Because of its ability to modulate other neurotransmitters, H3 receptor ligands are being
investigated for the treatment of numerous neurological conditions, including obesity,
movement disorders schizophrenia and ADHD and research is underway to determine
whether H3 receptor ligands could be useful in modulating wakefulness
There is also evidence that the H3-receptor plays an important role in Tourette syndrome.
other research demonstrated that reducing histamine concentration in the H3R causes tics,
but adding histamine in the striatum decreases the symptoms.
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17. H4 receptors
The discovery, at the turn of the millennium, that the histamine H4 receptor is
largely expressed in haemopoietic cells as well as its chemotactic properties
designate its regulatory role in the immune system. H4 receptors modulate
eosinophil migration and selective recruitment of mast cells leading to
amplification of histamine-mediated immune responses and eventually to chronic
inflammation..
H4 RECEPTOR
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18. H4 receptor involvement in dendritic cell activation and T cell differentiation
documents its immunomodulatory function. The characterization of the H4 as the
immune system histamine receptor directed growing attention towards its
therapeutic exploitation in inflammatory disorders, such as allergy, asthma,
chronic pruritus and autoimmune diseases. The efficacy of a number of
H4 receptor ligands has been evaluated in in vivo and in vitro animal models of
disease and in human biological samples
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19. Accumulating evidence derived from diverse in vivo and in vitro studies using
animal models of disease and human biological samples substantiates the
fundamental role of the H4 receptor in histamine-induced chemotaxis of MCs,
eosinophils and other immune cells. In addition, the presence of H4 receptors
mostly in immune system organs and their immunomodulatory role in cytokine
production argue for the pathophysiological significance of H4 receptors in
inflammatory conditions that are characterized by increases in immune cell
numbers, such as asthma, allergic disorders and autoimmune diseases and imply
their contribution not only in the histamine-mediated initial inflammatory signal
but also in the maintenance of inflammation
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20. PHARMACOLOGY
In clinical practice, currently there are few drugs that block the histamine H4
receptor activity selectively. The first potent and selective H4R antagonist,
JNJ7777120, was described in 2003 along with another selective H4R antagonist
that is a 7-NH2 substituted indolyl-piperazine derivative . Currently, several dozen
H4R ligands are known (most of these are antagonists); a large portion of them
were synthesized and described only recently
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21. Mast cell stabilizers are medications used to prevent or control certain allergic
disorders. They block mast cell degranulation, stabilizing the cell and thereby
preventing the release of histamine and related mediators. One suspected
pharmacodynamic mechanism is the blocking of IgE-regulated calcium channels.
Without intracellular calcium, the histamine vesicles cannot fuse to the cell
membrane and degranulate.
As inhalers they are used to treat asthma, as nasal sprays to treat hay fever
(allergic rhinitis) and as eye drops for allergic conjunctivitis Finally, in oral form,
they are used to treat the rare condition of mastocytosis.
MAST CELL STABILIZERS
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25. Dual acting agents are both histamine H1 antagonists and mast cell
stabilizers of these pro-inflammatory mast cell mediators is the first step
in the allergic cascade. E.g some generic names are
Epinastine
Emedastine
DUALACTING HISTAMINES
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