HISTAMINERGIC RECEPTORS

Classification : 4 types
1)
2)
3)
4)

H1 (Ash and Schil, 1966)

H2 ( Black et al ,1972)
H3 ( Arrang et al,1987)
H4 ( Hough , 2001)

H1 receptor
History

The first H1-antihistamine discovered was piperoxan, by Jeff Forneau and Daniel
Bovet (1933) in their efforts to develop a guinea pig animal-model for
anaphylaxis at Ryerson University. Bovet went on to win the 1957 Nobel Prize in
Physiology or Medicine for his contribution.
Histaminergic receptors were classified by Asch and Schild into H1 and H2 :
those blocked by then available antihistamines were labelled H1

Pharmacology
Histamine H1 receptor are G-protein-coupled receptors expressed throughout the body,
specifically 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) which
activates phospholipase C and the phosphatidylinositol (PIP2) signalling pathway.
Receptor Size - 487 AA

Function
1)Visceral Smooth muscle
Histamine causes bronchoconstriction, guinea pigs and patients of asthma are
highly sensitive.
It causes abdominal cramps and colic by increasing intestinal contractions.

2) Blood vessels--Histamine causes marked dilatation of smaller blood vessels, including arterioles,
capillaries and venules. Vasodilatation caused by histamine is partly indirect , mediated
through endothelium dependent relaxing factor : the receptor being located on the
endothelial cells.
Larger arteries and veins are constricted by histamine : mediated by H1 receptor
on vascular smooth muscle.
3)Sensory nerve endings-Stimulation- itching
4)Autonomic ganglia & adrenal medullaRelease of catecholamines, which can cause secondary rise in BP.
5)Brain

Histamine H1 receptors are activated by endogenous histamine, which is released

by neurons which have their cell bodies in the tuberomamillary neurons of the
hypothalamus.
The histaminergic neurons of the tubero-mammillary nucleus become active
during the 'wake' cycle, firing at approximately 2Hz;

During slow wave sleep this firing rate drops to approximately 0.5Hz.

Finally during REM sleep, histaminergic neurons stop firing all together.

It has been reported that histaminergic neurons have the most wakeselective firing pattern of all known neuronal types (Passani et al., 2004).
Thus Histamine, acting on H1-receptors, produces pruritus, vasodilatation,
hypotension, flushing, headache, tachycardia, bronchoconstriction, increases vascular
permeability, potentiates pain, and more. (Simons, 2004)

Agonist
2 -methylhistamine

Antagonists
First-generation H1-receptor antagonists

oldest antihistaminergic drugs and are relatively inexpensive

moderately to highly potent muscarinic acetylcholine receptor-antagonists
(anticholinergic) agents as well.
also commonly have action at -adrenergic receptors and/or 5-HT receptors

Ethylenediamines

mepyramine (pyrilamine)

Ethanolamines

diphenhydramine
carbinoxamine
doxylamine
clemastine
dimenhydrinate

Alkylamines

chlorphenamine (chlorpheniramine)
dexchlorphenamine
brompheniramine
triprolidine

Piperazines

cyclizine
chlorcyclizine
hydroxyzine
meclizine

Tricyclics
Doxapine HCl

Phenothiazines

Promethazine HCl

Piperidines
Cyprohepltadine HCl
Phenindamine tartrate

Second-generation H1-receptor antagonists

Newer drugs that are much more selective for peripheral H1 receptors in preference to
the central nervous system histaminergic and cholinergic receptors.

Systemic

cetirizine
loratadine
mizolastine
terfenadine (withdrawn from most markets due to risk of cardiac arrhythmias and
replaced with fexofenadine)
Ebastine

Topical

azelastine
levocabastine

Third-generation H1-receptor antagonists

1. Active enantiomer (levocetirizine) or metabolite (desloratadine &

fexofenadine) derivatives of second-generation drugs intended to have
increased efficacy with fewer adverse drug reactions.
2. A review by the Consensus Group on New Generation Antihistamines
concluded that none of the currently available antihistamines can be
classified as true Third-generation H1-receptor antagonists, which they
define as lacking in cardiotoxicity, drug-drug interactions andCNS effects
with possible beneficial effects ( e.g. antiinflammatory).
Levocetirizin
desloratadine
fexofenadine

H2 receptor
History
Sir James black (1972) developed the first H2 blocker burimamide and confirmed H2
receptor.

Pharmacology
H2 receptors positively coupled to adenylate cyclase via Gs. It is a potent stimulant of
cAMP production. It increases the intracellular Ca2+ concentrations and release Ca2+
from intracellular stores
Receptor Size - 359 AA

Location and Function

Gastric parietal cells (oxyntic cells) --- acid secretion

Vascular smooth muscle -- dilatation
Central nervous system --- transmitter
Heart --- +ve chronotropy, +ve inotropy
Uterus (Rat) -- Relaxation

Response

Stimulation of gastric acid secretion

Smooth muscle relaxation
Inhibit antibody synthesis, T-cell proliferation and cytokine production

Agonist
Dimaprit

Antagonists
cimetidine
ranitidine
famotidine
nizatidine
Roxatidine
Loxatidine

H3 receptor
History

H3 receptor was postulated by schwartz(1983)

H3 receptor was localised in a variety of cells using R--methylhistamine , a
selective H3 agonist, and thioperamide, an antagonist ( Arrang et al,1987)
1988 H3 receptor found to mediate inhibition of serotonin release in rat brain
cortex.
1997 H3 receptors shown to modulate ischemic norepinephrine release in animals.
1999 H3 receptor cloned
2000 H3 receptors called "new frontier in myocardial ischemia"

Locations & Functions of H3 receptors

1. Central nervous system- they act as autoreceptors in presynaptic
histaminergic neurons, and control histamine turnover by "feedback inhibition
of histamine synthesis and release as well."Thus it causes sedation.
2. Heart --depress exaggregated catecholamines release in the heart, e.g. during
ischemia.

3. Lungs inhibit H1 mediated broncoconstriction.

4. Gastrointestinal tract In the enterocromaffin like cells of the stomach,
H3 receptors inhibit gastrin induced release of histamine and, therefore ,
decrease HCl secreation mediated by H2 receptor.
5. Spleen , skin decrease hstamine content

Pharmacology

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.
The and subunits interact with N-type voltage gated calcium channels, to
reduce action potential mediated influx of calcium and hence reduce
neurotransmitter release.

Receptor Size - 373,365,445 AA

Isoforms
At least six H3 receptor isoforms in human is identified.

H3-receptor Agonists
Currently no therapeutic products selective for H3 receptors. Some, though not totally
selective, are:

R--methylhistamine
Immepip
imetit
o Addition of methy groups to the and side chain of histamine can result
in potent H3-receptor agonists.

H3-receptor Antagonists

Thioperamide
Clobenpropit

H4 receptor

History
The H4 histamine receptor was discovered by Hough, 2001.
Like the other three histamine receptors, it is also a G protein-coupled receptor.
Receptor Size - 390 AA

Location
H4 is highly expressed in bone marrow and white blood cells ( cells of hematopoietic
origin)and regulates zymosan-induced neutrophil release from bone marrow. It is also
expressed in the colon, liver, lung, small intestine, spleen, testes, thymus, tonsils, and
trachea.

Functions
They have been shown to mediate mast cell chemotaxis

AgonistsClobenpropit (partial? )
AntagonistsJNJ7777120
Thioperamide

Reference

Randal A.S., Ervin G.E.: Histamine , Bradykinin, And their Antagonists, in

Goodman & Gilman s The Pharmacological Basis of THERAPEUTICS 11th
edition, 629-652
Behavioral Characterization of Mice Lacking Histamine H3 Receptors
Passani MB, Lin JS, Hancock A, Crochet S, Blandina P. The histamine H3
receptor as a novel therapeutic target for cognitive and sleep disorders. Trends
Pharmacol Sci. 2004 Dec;25(12):618-25.
Tuan Nguyen, David A. Shapiro, Susan R. George, Vincent Setola, Dennis K.
Lee, Regina Cheng, Laura Rauser, Samuel P. Lee, Kevin R. Lynch, Bryan L.
Roth, and Brian F. O'Dowd Discovery of a Novel Member of the Histamine
Receptor Family The Journal of Molecular Pharmacology Vol. 59, Issue 3, 427433, March 2001