HISTAMINE

Chemistry and Pharmacokinetics

The formation of histamine occurs by the removal of a carboxyl group (decarboxylation) from amino acid L-histidine.

Histamine is active biologically, but the first step for its inactivation involves the addition of a methyl group (CH3) followed by a chemical oxidation.

Histamine mediates its effects by interacting with intracellular G protein receptors include H1, H2, H3 and H4 types:

Receptor

SubtypeLocalizationReceptor coupling

Antagonists (partially selective)

H1

Endothelium, brain, smooth muscle

receptor activation causes and increased

IP3, DAG (diacylglycerol) 

production  

N/A

H2

mass and cells, gastric

mucosa, cardiac muscle, brain

receptor activation causes an  increase in

cAMP production 

ranitidine (Zantac),

cimetidine (Tagamet)

H3presynaptic: brain,

mesenteric plexus (other

G protein coupledN/A

neurons)BUT H4 is highly expressed in bone marrow and white blood cells and regulates neutrophil release from bone marrow, also expressed in the colon, liver, lung, small intestine, spleen, testes, thymus, tonsils, and trachea.

Histamine Clinical uses:

o  Pulmonary Function: histamine aerosol may be used to test for bronchial hyperreactivity.

  Toxicities:

o  Flushing, hypotension, tachycardia, headache, bronchoconstriction, gastrointestinal disturbance.

o  Should not be given to asthmatics (except with extreme caution in pulmonary function testing).

o  Should not be given to patients with active ulcer disease or gastrointestinal hemorrhage.

Histamine antagonists:

physiologic antagonists: epinephrine, agents that produce opposing effects, acting and different receptors.

release inhibitors: reduced mast cell degranulation: cromolyn and nedocromil.

receptor antagonists: selective blockade of histamine receptors.

H1 receptor antagonists:

1st generation

SAR:

Two aromatic rings, connected to a central carbon, nitrogen or CO

Spacer between the central X and the amine, usually 2–3 carbons in length, linear, ring, branched, saturated or unsaturated

Amine is substituted with small alkyl groups, e.g., CH3

X = N, R1 = R2 = small alkyl groupsX = CX = CO

Chirality at X can increase both the potency and selectivity for H1-receptors

For maximum potency, the two aromatic rings should be orientated in different planes for example, tricyclic ring system is slightly puckered

and the two aromatic rings lie in different geometrical planes, giving the drug a very high potency

classes:

ClassDescriptionExamples

Ethylenediamines

Ethylenediamines were the first group of clinically effective H1-antihistamines developed.

Mepyramine(pyrilamine)

Antazoline

Tripelennamine

Ethanolamines

Diphenhydramine was the prototypical agent in this group. Significant anticholinergic adverse effects, as well as sedation, are observed in this group but the incidence of gastrointestinal adverse effects is relatively low.[3][6]

Diphenhydramine

Carbinoxamine

Doxylamine

Orphenadrine

Bromdiphenhydramine

Clemastine

Dimenhydrinate

Alkylamines

The isomerism is a significant factor in the activity of the agents in this group. E-triprolidine, for example, is 1000-fold more potent than Z-triprolidine. This difference relates to the positioning and fit of the molecules in the histamine H1-receptor binding site.

Pheniramine

Chlorphenamin

e(chlorpheniramine)

Dexchlorpheniramine

Dexbrompheniramine

Brompheniramine

Triprolidine

Dimetindene

PiperazinesThese compounds are structurally related to the ethylenediamines and the ethanolamines, and produce significant anticholinergicadverse effects. Compounds from this group are often used for motion sickness, vertigo, nausea,

Cyclizine

Chlorcyclizine

Hydroxyzine

Meclizine

and vomiting. The second-generation H1-antihistamine cetirizine also belongs to this chemical group.[6]

Tricyclics and Tetracyclics

These compounds differ from the phenothiazine antipsychotics in the ring-substitution and chain characteristics.[6] They are also structurally related to the tricyclic antidepressants (and tetracyclics), explaining the H1-antihistaminergic adverse effects of those three drug classes and also the poor tolerability profile of tricyclic H1-antihistamines. The second-generation H1-antihistamine loratadine was derived from compounds in this group.

Promethazine

Alimemazine(trimeprazine)

Cyproheptadine

Azatadine

Ketotifen

Ethylenediamines

Ex. Antazoline

N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-N-(phenylmethyl)aniline

*Antazoline is first generation antihistamine that also has anticholinergic properties.

Trade name: Vasocon-a

Uses: nasal decongesion, eye drops for allergic conjunctivitis.

Ethanolamines

1) Diphenhydramine

2-(diphenylmethoxy)-N,N-dimethylethanamine

Trade names

Benadryl, Unisom, Sominex

Possessing anticholinergic, antitussive, antiemetic & sedative properties which is mainly used to treat allergies.

Like most other first G antihistamines has powerful hypnotic effect>>use in Sleep Aid.

can act as antiparkinson agent as a result of blocking muscarinic acetylcholine in Brain.

2) Carbinoxamine

2-[(4-chlorophenyl)-pyridin-2-yl-methoxy]-N,N-dimethyl-ethanamine

Trade name >Clistin, Palgic, Rondec, Rhinopront*

*approved only for adults or children ages 3 or older.

Alkylamines

Pheniramine

N,N-dimethyl-3-phenyl-3-pyridin-2-yl-propan-1-amine

Trade name>Avil

2 (Chlorphenamine (INN) or Chlorpheneramine

3(-4-chlorophenyl-)N,N-dimethyl-3-pyridin-2-yl-propan-1-amine

Trade name>Chlorphen (chlorphenamine maleate )

*Its sedative effects are relatively weak compared to other first-generation antihistamines.

*has antidepressant or anti-anxienty effect but not approved as medication for these cases.

*it's haloginated alkylamine >exhibit optical isomerism>>used as racemic mixture

3 )Dexchlorpheniramine

)3S-(3-(4-chlorophenyl)-N,N-dimethyl-3-pyridin-3-ylpropan-1-amine

Trade name>>Chlor-trimeton

*Active isomer is dextrorotatory isomer

*has no adv. Over the parent chlorpheneramine.

Piperazines

1 (Cyclizine

1-benzhydryl-4-methyl-piperazine

Trade names

Marezine, Valoid, Nausicalm

Uses>

N/V & dizziness associated with motion sickness & vertigo.

The precise mechanism of action in inhibiting the symptoms of motion sickness is not well understood.

It may have effects directly on the labyrinthine apparatus and on chemoreceptor trigger zone.

2 )Meclozine

RS)-1-[(4-chlorophenyl)(phenyl)methyl]-4-(3-methylbenzyl)piperazine

Trade name> Bonine, Bonamine, Antivert, Postafen

*an anatihistaminic considered to be anti emetic.

*has shorter half life than Cyclizine.

The drug depresses labyrinth excitability and vestibular stimulation, and it may affect the medullary chemoreceptor trigger zone.

----------------------------------------------------------------------------------------------

Tricyclics and Tetracyclics

1 (Promethazine

(RS-)N,N-dimethyl-1-(10H-phenothiazin-10-yl)propan-2-amine

Trade name> Promethegan, Romergan

*is a first G antihistamine of the Phenothiazine family

*uses>> sedative,,for hay fever.

Second-generation Second-generation H1-antihistamines are newer drugs that

are much more selective for peripheral H1 receptors as opposed to the central nervous system H1 receptors and cholinergic receptors. This selectivity significantly reduces the occurrence of adverse drug reactions, such as sedation, while still providing effective relief of allergic conditions. The reason for their peripheral selectivity is that most of these compounds are zwitterionic at physiological pH (around pH 7.4). As such, they are very polar, meaning that they do not cross the blood–brain barrier and act mainly outside the central nervous system.

Systemic:

Astemizole

1-[(4-fluorophenyl)methyl]- N-[1-[2- (4 methoxyphenyl -

)ethyl]- 4-piperidyl]benzoimidazol-2-amine

Brand name Hismanal

Pharmacology

Astemizole is a histamine H1-receptor antagonist. It is structurally similar to terfenadine and haloperidol (a butyrophenoneantipsychotic). It has anticholinergic and antipruritic effects.

Astemizole competitively binds to histamine H1-receptor sites in the gastrointestinal tract, uterus, blood vessels, and bronchial muscle. This suppresses the formation of edema and pruritus (caused by histamine).

Astemizole does not cross the blood–brain barrier, and H1 receptor binding is mostly in the peripheral rather than central nervous system (CNS depression is thus minimal). Astemizole may also act on histamine H3 receptors, thereby producing adverse effects.

Astemizole does also act as FIASMA (functional inhibitor of acid sphingomyelinase).[2]

Astemizole is rapidly absorbed from the gastrointestinal tract; protein binding is around 96 percent.

Astemizole may cause life-threatening arrhythmia.

Ketotifen

 

4-(1-methylpiperidin-4-ylidene)-4,9-dihydro-10H-benzo[4,5]cyclohepta[1,2-b]thiophen-10-one

Brand names: Zaditor/Zaditen (Novartis), Alaway (Bausch and Lomb),Zyrtec Itchy Eye Drops, and Claritin Eye.

 Uses:

available in two forms. In its ophthalmic form, it is used to treat allergic conjunctivitis,[1] or the itchy red eyes caused by allergies. In its oral form, it is used to prevent asthma attacks. Side effects include

drowsiness, weight gain, dry mouth, irritability, and increased nosebleeds.

Cetirizine

(±)-[2-[4-[(4-chlorophenyl)phenylmethyl]-1- piperazinyl]ethoxy]acetic acid

Brand names:  Zyrtec and Reactine

major metabolite of hydroxyzine, and a racemic selective H1receptor inverse agonist used in the treatment of allergies, hay fever, angioedema, and urticaria.

Pharmacology:

Cetirizine crosses the blood–brain barrier only slightly, reducing the sedative side-effect common with older antihistamines

inhibit eosinophil chemotaxis and LTB4 release. At a dosage of 20 mg.

The levorotary enantiomer of cetirizine, known as levocetirizine, is the more active form.

L-Stereoisomer, levocetirizine(top) and D-stereoisomer of cetirizine

Loratadine

Ethyl 4-(8-chloro-5,6-dihydro-11H-

benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate

Structurally, it is closely related totricyclic antidepressants, such as imipramine, and is distantly related to the atypical antipsychotic quetiapine.[1]

trade names:

Claritin In  Claritin-D or Clarinase, it is combined

withpseudoephedrine, a decongestant; this makes it useful for colds as well as allergies but adds potential side-effects of insomnia,anxiety, and nervousness.

acts as a selective inverse agonist of peripheral histamine H1-receptors.[5] Histamine is responsible for many features of allergic reactions.

Rupatadinetrade names such as Rupafin, Alergoliber, Rinialer, Pafinur, Rupax and 

Ralif. 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine fumarate

Rupatadine is a second generation, non-sedating, long-acting histamine antagonist with selective peripheral H1 receptor antagonist activity. It further blocks the receptors of the platelet-activating factor (PAF)

 possesses anti-allergic properties such as the inhibition of the degranulation of mast cells induced by immunological and non-immunological stimuli, and inhibition of the release of cytokines, particularly of the TNF in human mast cells and monocytes

Mizolastine

2-[{1-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]piperidin-4-yl}(methyl)amino]pyrimidin-4(1H)-one

Trade name: Mezollin.

 non-sedating antihistamine. It blocks H1 receptors and is commonly fast-acting. It does not prevent the actual release of histamine from mast cells, just prevents it binding to receptors.

Acrivastine

 

(E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidin-1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoic acid

Trade name Benadryl Allergy Relief 

Ebastine

4-(4-benzhydryloxy-1-piperidyl)-1-(4-tert-butylphenyl)butan-1-one

trade names Evastin, Kestine, Ebastel, Aleva

does not penetrate the blood–brain barrier and thus allows an effective block of the H1 receptor in

peripheral tissue without a central side effect, i.e. not causing sedation or drowsiness.

E structure that differs from other second generation antihistamines. After oral administration, ebastine undergoes extensive first-pass metabolism by hepatic cytochrome P450 3A4 into its active carboxylic acid metabolite, carebastine. This reaction has a conversion rate of 100%.

Bilastine

2-[4-(2-{4-[1-(2-Ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidinyl} ethyl) phenyl]-2-

methylpropanoic acid

tradename: Bilaxten 

effective in the treatment of ocular symptoms and diseases of allergies, including rhinoconjuctivitis

Bepotastine

4-[4-[(4-chlorophenyl)-pyridin-2-ylmethoxy]piperidin-1-yl]butanoic acid

Trade name: (Talion)

 ophthalmic preparation

Terfenadine

(RS)-1-(4-tert-butylphenyl)-4-{4-[hydroxy(diphenyl)methyl]piperidin-1-yl}-butan-1-ol

brand names: Seldane in the United States, Triludan in the United Kingdom, and Teldane in Australia

Terfenadine is a prodrug, generally completely metabolized to the active form fexofenadine in the liver by the enzyme cytochrome P450CYP3A4 isoform. Due to its near complete metabolism by the liver immediately after leaving the gut, terfenadine normally

is not measurable in the plasma. Terfenadine itself, however, is cardiotoxic at higher doses, while its major active metabolite is not.

Topical:

Azelastine

(RS)-4-[(4-chlorophenyl)methyl]-2- (1-methylazepan-4-yl)-phthalazin-1-one

 formulated both as a nasal spray (0.1% and 0.15% solutions) and as eye drops (0.05% solution)

Brand names:

nasal spray  Allergodil (Europe),Rhinolast in the UK, Astelin/Astepro in the US, and Azep in Australia.

eye drops have been launched in over 30 countries including the UK (Optilast) and the USA (Optivar). Azelastine has a triple mode of action:[8]

1. Anti-histamine effect,2. Mast-cell stabilizing effect and3. Anti-inflammatory effect.

Azelastine has a rapid onset of action; 15 minutes with the nasal spray[6] and 3 minutes with the eye drops.[9] The effect lasts for 12 hours.[10]

Azelastine is oxidatively metabolized by the cytochrome P450 family into its active metabolite,

desmethylazelastine, and two inactive carboxylic acid metabolites. Approximately 75% of an oral dose is excreted in feces. Pharmacokinetics of orally administered azelastine are not affected by age, gender or hepatic impairment

Levocabastine

(3S,4R)-1-[4-cyano-4-(4-fluorophenyl)cyclohexyl]-3-methyl-4-phenylpiperidine-

4-carboxylic acidAs well as acting as an antihistamine, levocabastine has also subsequently been found to act as a potent and selective antagonist for the neurotensin receptor NTS2, and was the first drug used to characterise the different neurotensin subtypes.

Olopatadine

{(11Z)-11-[3-(dimethylamino)propylidene]-6,11-

dihydrodibenzo[b,e]oxepin-2-yl}acetic acid

antihistamine (as well as anticholinergic) and mast cell stabilizer

 trade name:

Pataday  It is used to treat itching associated with allergic conjunctivitis (eye allergies).

Olopatadine hydrochloride 0.1% is sold as Patanol (or Opatanol in some countries). A nasal spray.

It should not be used to treat irritation caused by contact lenses.

Its side effects may include headaches (7% of occurrence) burning and stinging (5%), dry eye, foreign body sensation, hyperemia,keratitis, lid edema, pruritus, asthenia, cold syndrome, pharyngitis, rhinitis, sinusitis, and taste perversion.

Third-generation

Third-generation H1-antihistamines are the active enantiomer (levocetirizine) or metabolite (desloratadine & fexofenadine) derivatives of second-generation drugs intended to have increased efficacy with fewer adverse drug reactions. Indeed, fexofenadine is associated with a decreased risk of cardiac arrhythmia compared to terfenadine.

Systemic:

Levocetirizine

2-(2-{4-[(R)-(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl}ethoxy)acetic acid

 brand name: Xyzal

non-sedative (does not enter the brain in significant amount), developed from the second-generation antihistamine cetirizine. Chemically, levocetirizine is the active enantiomer of cetirizine. It is the R-enantiomer of the cetirizine racemate. Levocetirizine works by blocking histamine receptors. It does not prevent the actual release of histamine from mast cells, but prevents it binding to its receptors. This in turn prevents the release of other allergy chemicals and increased blood supply to the area, and provides relief from the typical symptoms of hay fever.

Desloratadine

. 8-chloro-6,11-dihydro-11-(4-piperdinylidene)- 5H-benzo[5,6]cyclohepta[1,2-

b]pyridine

Trade names: NeoClarityn, Claramax, Clarinex,Larinex, Aerius, Dazit, Azomyr, Deselex and Delot.

Desloratadine is a tricyclic antihistamine, which has a selective and peripheral H1-antagonist action. It is an antagonist at histamine H1 receptors, and an antagonist at all subtypes of the muscarinic acetylcholine receptor. It has a long-lasting effect and in moderate and low doses, does not cause drowsiness because it does not readily enter the central nervous system.[2] Unlike other antihistamines, desloratadine is also effective in relieving nasal congestion, particularly in patients with allergic rhinitis. [3]

Desloratadine vs. loratadine

Desloratadine is the major metabolite of loratadine. There are no head-to-head randomised controlled trials of the two drugs. A survey of patients dissatisfied with loratadine published in August 2003 reported equal or better satisfaction with desloratadine,[4] concluding:

When severity of disease was controlled for in the analysis, a pattern emerged suggesting greater levels of satisfaction amongst loratadine dissatisfied patients who converted to desloratadine. Point estimates suggest a consistent pattern favoring desloratadine patient satisfaction, with statistically significant results reported for sum of adverse effects, nighttime awakening due to symptoms, symptom severity just prior to the next dose, and overall satisfaction (p < 0.05)

H2 antagonist

History and development

Cimetidine was the prototypical histamine H2-receptor antagonist from which the later members of the class were developed

The SK&F team used a classical design process starting from the structure of histamine. Hundreds of modified compounds were synthesised in an effort to develop a model of the then-unknown H2 receptor. The first breakthrough was Nα-guanylhistamine, a partial H2-receptor antagonist. From this lead the receptor model was further refined and eventually led to the development of burimamide, a specific competitive antagonist at the H2 receptor 100-times more potent than Nα-guanylhistamine.

Pharmacology

The H2 antagonists are competitive antagonists of histamine at the parietal cell H2 receptor. They suppress the normal secretion of acid by parietal cells and the meal-stimulated secretion of acid. They accomplish this by two mechanism: Histamine released is blocked from binding on parietal cell H2 receptors, which stimulate acid secretion; therefore, other substances that promote acid secretion (such as gastrin and acetylcholine) have a reduced effect on parietal cells when the H2 receptors are blocked.

General Clinical uses :

H2-antagonists are used by clinicians in the treatment of acid-related Gastrointestinal conditions. To be specific, these indications may include:

Peptic ulcer disease (PUD)

Gastroesophageal reflux disease (GERD/GORD)

Dyspepsia

Prevention of stress ulcer (a specific indication of ranitidine)

Adverse effects

H2 antagonists are, in general, well tolerated, except for cimetidine, where in all of the following adverse drug reactions (ADRs) are common. Infrequent ADRs include hypotension. Rare ADRs include: headache, tiredness, dizziness, confusion, diarrhea, constipation, and rash.

Burimamide

1-[4-(1H-Imidazol-5-yl)butyl] -3-methylthiourea

A highly specific competitive antagonist at the H2 receptor 100-times more potent than Nα-guanylhistamine, it has H3 blocking action. but its inactive in physiological pH due to the presence of its electron donating side chain

Replacement of guanidine gp with thiourea , increasing carbon chain to four carbon has result in better fitting to receptor because it moves thiourea gp closer to the antagonist binding site

Not used

Metiamide

N-methyl-N'-(2-{[(4-methyl-1H-imidazol-5-yl)methyl]thio}ethyl)thiourea

developed from another H2 antagonist, burimamide

The addition of a sulfide group close to the imidazole ring, the addition of methyl group to the 4- position on the imidazole ring more selectivity to H2 receptor.

It was determined that the thiourea group was the cause of the agranulocytosis. Therefore replacement of the =S in the thiourea group was suggested

Not used because was associated with unacceptable nephrotoxicity and agranulocytosis

Cimetidine

2-cyano- 1-methyl- 3-(2-[(5-methyl- 1H-imidazol- 4-yl)methylthio]ethyl)guanidine

Adding a -C≡N or -NO2 group prevented the guanidine group being protonated and did not cause agranulocytosis

The nitro and cyano groups are sufficiently electrwithdrawing to decrease basicty and ionization of the neighbouring nitrogens to the same acidity of the thiourea group, hence preserving the activity of the drug in a physiological environment.

Metabolized by and  inhibit of the P450 because imidazole group chelates Fe of heme in cyp 450 result in significant drug interactions and in rare instances of clinically apparent acute liver injury.

Cimetidine has been found to possess clinically significant anti-androgen properties at high doses that are especially noticeable in men

Cimetidine's anti-androgen properties likely explain certain side effects seen with it such as galactorrhea and amenorrhea in women and gynecomastia and impotence in men

Ranitidine

N-(2-[(5-(dimethylaminomethyl)furan- 2-yl)methylthio]ethyl)- N-methyl- 2-nitroethene- 1,1-diamine

Last longer than cimiditine and with less side effect because it's weak inhibitor of cytochrome P-450

Ten times the activity of cimiditine

SAR :

Replacing the sulfur atom with a methylene unit leads to a drop in activity

Placing the sulfur next to ring lowers activity

Replacing the furan with more hydrophobic rings such as phenyl or thiophene reduces activity

2,5- disubstitution is the best substitution pattern for the furan ring

Methy substitution at C3 of furan eliminates activity whereas

the equivalent substitution in the imidazole series increase activity

Methyl substitution at C4 of furan ring increases activity

Famotidine

3-([2-(diaminomethyleneamino)thiazol- 4-yl]methylthio)- N'-sulfamoylpropanimidamide

Competitive histamine H2-receptor antagonist

Replacing imidazole ring of cimetidine with 2-guanidinothiazole ring.

Sulfonylamidine is not essential can be replaced with other structures as long as they are planer

Optimum activity chain length four or five units

Replace sulfa with CH2 gp increase activity

No cyp 450 effect

SAR of H2 receptor antagonist :

H2 receptor antagonist must bind but not activate H2 receptor sit

1) Addition of aromatic ring: Basic heterocycle group as imidazole

2) Addition of non-polar, hydrophobic substituents like Flexible chain or aromatic ring

3) Addition of a functional group to bind with another binding region and prevent the conformational change like polar group system.

Above structure of Na –Guanylhistamine shows first antagonist property.

4 (The imidazole ring of histamine is not required for competitive antagonism of histamine at H2-receptors. Other heterocyclic rings (furan, thiophene, thiazole, etc.) may be

used.

5) Separation of the ring and the nitrogen group with the equivalent of a four carbon chain appears to be necessary for optimum antagonist activity. The isosteric thioether link is acceptable, CH3 on C4 gives H2 selectivity .

6) The terminal nitrogen group should be polar, non-basic ,substituents should be stronger electron withdrawing group for maximal antagonist activity

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 also control histamine turnover by feedback inhibition of histamine synthesis and release.[1] 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, and serotonin.

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.[2]

Pharmacology

[edit] 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:

(R)-α-methylhistamine

Cipralisant

Antagonists

Betahistine

N-methyl-2-(pyridin-2-yl)ethanamine

uses :

antivertigo drug. It was first registered in Europe in 1970 for the treatment of Ménière's disease. It is commonly prescribed to patients with balance disorders or to alleviate vertigo symptoms associated with Ménière's disease

Burimamide

Ciproxifan

cyclopropyl 4-(3-(1H-imidazol-4-yl)propyloxy)phenyl ketone

Histamine H4 receptor

Tissue distribution

H4 is expressed primarily in the bone marrow and eosinophils. Shows preferential distribution in cells of immunological relevance such as T-cells, monocytes, mast cells. and regulates neutrophil release from bone marrow. It is also expressed in the colon, liver, lung, small intestine, spleen, testes, thymus, tonsils, and trachea.

Function

They have been shown to mediate mast cell chemotaxis.it seems to do this by the mechanism of Gi-coupled decrease incAMP.

Structure

The 3D structure of the H4 receptor has not been solved yet due to the difficulties of GPCR ( G protein-coupled receptor )crystallization. 

. During the search for histamine H4-receptor ligands, It was clear that there is considerable overlap in the pharmacology of h3 and H4 receptor. High affinity h3 agonist 4 methyhistamine has H4 agonist properties although their relative potency with respect to histamine is generally lower .

The H3 receptor antagonist clobenpropit also binds with high affinity to the H4 receptor but also possesses weak H4

agonist activity . Thioperamide is an antagonist at both the h3 and H4 receptor but has 5 to 10 fold lower affinity for H4 also has inverse agonist activity at both receptor .The most striking aspect of the pharmacology of the new H4 receptor however is the fact that atypical antipsychotic drug clozapine has a partial agonist activity at the H4

receptor but no agonist or antagonist activity at the h3 receptor.

Agonists

4-Methylhistamine

2-(5-methyl-1H-imidazol-4-yl)ethanamine

VUF-8430

 

(2-[(Aminoiminomethyl)amino]ethyl carbamimidothioic acid ester)

Antagonists

Thioperamide

N-Cyclohexyl-4-(1H-imidazol-4-yl)piperidine-1-carbothioamide

Capable of crossing the blood–brain barrier.

JNJ 7777120

5-chloro-2-[(4-methylpiperazin-1-yl)carbonyl]-1H-indole

First potent and selective non-imidazole H4 antagonist

It displays high affinity and is more than 1000-fold selective for H4 over other histamine receptors . It has antiinflammatory effects, and has been demonstrated to be superior to traditional antihistamines in the treatment of pruritus (itching).

. A potential H4 antagonist drug is currently being tested in a phase II clinical trial.

VUF-6002

5-Chloro-2-[(4-methylpiperazin-1-yl)carbonyl]-1H-benzimidazole

 Orally active and inhibits the activity of both mast cells and eosinophils in vivo, and has antiinflammatory.