You are on page 1of 37


Chemistry and Pharmacokinetics

The formation of histamine occurs by the removal of a carboxyl group (decarboxylation) from amino acid Lhistidine. 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 Localization Subtype Antagonists (partially selective) N/A

Receptor coupling




Endothelium, receptor activation causes brain, and increased IP3, DAG smooth (diacylglycerol) muscle production mass and cells, gastric receptor activation causes mucosa, an increase in cAMP cardiac production muscle, brain presynaptic: brain, mesenteric G protein coupled plexus (other neurons)

ranitidine (Zantac), cimetidine (Tagamet)


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 groups X=C X = 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

[6]    Mepyramine(pyrilamine) Antazoline Tripelennamine Diphenhydramine Carbinoxamine Doxylamine Orphenadrine Bromdiphenhydramine Clemastine Dimenhydrinate Pheniramine Chlorphenamine(chlorphenir amine) Dexchlorpheniramine Dexbrompheniramine Brompheniramine Triprolidine Dimetindene          Alkylamines          Cyclizine Chlorcyclizine Hydroxyzine Meclizine Piperazines . Compounds from this group are often used for motion sickness.classes: Class Description Examples Ethylenediamines were the Ethylenediami first group of clinically nes effective H1-antihistamines developed. and vomiting. as well as s sedation. Diphenhydramine was the prototypical agent in this group. for example.[3][6] The isomerism is a significant factor in the activity of the agents in this group. This difference relates to the positioning and fit of the molecules in the histamine H1-receptor binding site. Significant anticholinergic ad Ethanolamine verse effects. vertigo. nausea. The secondgeneration H1antihistamine cetirizine also belongs to this chemical group. and produce significant anticholinergicadv erse effects. are observed in this group but the incidence of gastrointestinal adverse effects is relatively low. E-triprolidine. These compounds are structurally related to the ethylenediamines and the ethanolamines. is 1000-fold more potent than Z-triprolidine.

These compounds differ from the phenothiazine antipsych otics in the ring-substitution and chain characteristics. The second-generation H1antihistamine loratadine was derived from compounds in this group. Antazoline N-(4.[6] They are also structurally related to the tricyclic antidepressants (and tetracy Tricyclics and clics).5-dihydro-1H-imidazol-2-ylmethyl)N-(phenylmethyl)aniline *Antazoline is first generation antihistamine that also has anticholinergic properties. explaining the H1Tetracyclics antihistaminergic adverse effects of those three drug classes and also the poor tolerability profile of tricyclic H1-antihistamines. .      Promethazine Alimemazine(trimeprazine) Cyproheptadine Azatadine Ketotifen Ethylenediamines Ex. Trade name: Vasocon-a Uses: nasal decongesion. eye drops for allergic conjunctivitis.

antiemetic & sedative properties which is mainly used to treat allergies. can act as antiparkinson agent as a result of blocking muscarinic acetylcholine in Brain. Sominex Possessing anticholinergic.N-dimethylethanamine Trade names Benadryl. Unisom. antitussive. Like most other first G antihistamines has powerful hypnotic effect>>use in Sleep Aid. 2) Carbinoxamine .Ethanolamines 1) Diphenhydramine 2-(diphenylmethoxy)-N.

N-dimethyl-3-phenyl-3pyridin-2-yl-propan-1amine Trade name>Avil 2) Chlorphenamine (INN) or Chlorpheneramine . Rondec. Alkylamines Pheniramine N. Palgic.Ndimethyl-ethanamine *Trade name >Clistin. Rhinopront *approved only for adults or children ages 3 or older. 2-[(4-chlorophenyl)-pyridin-2-yl-methoxy]-N.

N-dimethyl-3pyridin-3-ylpropan-1-amine Trade name>>Chlor-trimeton *Active isomer is dextrorotatory isomer *has no adv. Piperazines . *it's haloginated alkylamine >exhibit optical isomerism>>used as racemic mixture 3) Dexchlorpheniramine (3S)-3-(4-chlorophenyl)-N. *has antidepressant or anti-anxienty effect but not approved as medication for these cases. Over the parent chlorpheneramine.3-(4-chlorophenyl)-N.N-dimethyl-3pyridin-2-yl-propan-1-amine Trade name>Chlorphen (chlorphenamine maleate ) *Its sedative effects are relatively weak compared to other first-generation antihistamines.

Nausicalm Uses> N/V & dizziness associated with motion sickness & vertigo. 2) Meclozine . Valoid. 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.1) Cyclizine 1-benzhydryl-4-methyl-piperazine Trade names Marezine.

and it may affect the medullary chemoreceptor trigger zone.RS)-1-[(4-chlorophenyl)(phenyl)methyl]-4-(3methylbenzyl)piperazine Trade name> Bonine. *has shorter half life than Cyclizine. The drug depresses labyrinth excitability and vestibular  stimulation. Postafen *an anatihistaminic considered to be anti emetic. Antivert. Bonamine. ---------------------------------------------------------------------------------------------  Tricyclics and Tetracyclics .

N-dimethyl-1-(10H-phenothiazin-10-yl)propan-2-amine Trade name> Promethegan. Second-generation .for hay fever..1) Promethazine (RS)-N. Romergan *is a first G antihistamine of the Phenothiazine family *uses>> sedative.

Astemizole does not cross the blood–brain barrier. Astemizole may also act on histamine H3 receptors. and bronchial muscle. Astemizole competitively binds to histamine H1-receptor sites in the gastrointestinal tract. Systemic: Astemizole 1-[(4-fluorophenyl)methyl]. This suppresses the formation of edema and pruritus (caused by histamine). while still providing effective relief of allergic conditions. such as sedation. . 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. thereby producing adverse effects.4piperidyl]benzoimidazol-2-amine Brand name Hismanal Pharmacology Astemizole is a histamine H1-receptor antagonist.(4 methoxyphenyl - )ethyl]. The reason for their peripheral selectivity is that most of these compounds are zwitterionic at physiological pH (around pH 7. It is structurally similar to terfenadine and haloperidol (a butyrophenoneantipsychotic). blood vessels. meaning that they do not cross the blood–brain barrier and act mainly outside the central nervous system. they are very polar. uterus. and H1 receptor binding is mostly in the peripheral rather than central nervous system (CNS depression is thus minimal).4). This selectivity significantly reduces the occurrence of adverse drug reactions. It has anticholinergic and antipruritic effects.N-[1-[2. As such.

protein binding is around 96 percent. dry mouth. In its oral form. Alaway (Bausch and Lomb). and increased nosebleeds.9-dihydro-10Hbenzo[4. Uses: available in two forms. irritability.5]cyclohepta[1.[2] Astemizole is rapidly absorbed from the gastrointestinal tract. Ketotifen 4-(1-methylpiperidin-4-ylidene)-4. Astemizole may cause life-threatening arrhythmia.[1] or the itchy red eyes caused by allergies. it is used to treat allergic conjunctivitis. . In its ophthalmic form. and Claritin Eye.Astemizole does also act as FIASMA (functional inhibitor of acid sphingomyelinase). it is used to prevent asthma attacks.Zyrtec Itchy Eye Drops.2-b]thiophen-10-one Brand names: Zaditor/Zaditen (Novartis). Side effects include drowsiness. weight gain.

angioedema. At a dosage of 20 mg. The levorotary enantiomer of cetirizine. and a racemic selective H1receptor inverse agonist used in the treatment of allergies. levocetirizine(top) and D-stereoisomer of cetirizine Loratadine . reducing the sedative side-effect common with older antihistamines inhibit eosinophil chemotaxis and LTB4 release. and urticaria. L-Stereoisomer. Pharmacology:    Cetirizine crosses the blood–brain barrier only slightly. hay fever. known as levocetirizine. is the more active form. Cetirizine (±)-[2-[4-[(4-chlorophenyl)phenylmethyl]-1piperazinyl]ethoxy]acetic acid Brand names: Zyrtec and Reactine  major metabolite of hydroxyzine.

a decongestant. Pafinur. such as imipramine. acts as a selective inverse agonist of peripheral histamine H1-receptors.6]cyclohepta[1. Rinialer. it is closely related totricyclic antidepressants.  Rupatadine trade names such as Rupafin.anxiety.2-b]pyridin-11ylidene)-1-piperidinecarboxylate Structurally. this makes it useful for colds as well as allergies but adds potential side-effects of insomnia.6-dihydro-11H- benzo[5.[5] Histamine is responsible for many features of allergic reactions. it is combined withpseudoephedrine. Alergoliber. and nervousness.[1] trade names:  Claritin In  Claritin-D or Clarinase. Rupax and . and is distantly related to the atypical antipsychotic quetiapine.Ethyl 4-(8-chloro-5.

8-Chloro-6. particularly of the TNF in human mast cells and monocytes  Mizolastine 2-[{1-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]piperidin4-yl}(methyl)amino]pyrimidin-4(1H)-one Trade name: Mezollin.2-b]pyridine fumarate Rupatadine is a second generation.6]cyclohepta[1. It blocks H1 receptors and is commonly fast-acting. just prevents it binding to receptors.Ralif. longacting histamine antagonist with selective peripheral H1 receptor antagonist activity. non-sedating antihistamine.11-dihydro-11-[1[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5Hbenzo[5. It does not prevent the actual release of histamine from mast cells. non-sedating. . and inhibition of the release of cytokines. 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.

E structure that differs from other second generation antihistamines. i. not causing sedation or drowsiness. Acrivastine (E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidin-1-ylprop-1-enyl]pyridin-2-yl}prop-2-enoic acid Trade name Benadryl Allergy Relief  Ebastine 4-(4-benzhydryloxy-1piperidyl)-1-(4-tert-butylphenyl)butan-1-one trade names Evastin. After oral administration. ebastine undergoes extensive first-pass metabolism by hepatic cytochrome P450 3A4 into its active carboxylic acid metabolite. Kestine. . 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.e. Ebastel. This reaction has a conversion rate of 100%. carebastine.

 Bilastine 2-[4-(2-{4-[1-(2-Ethoxyethyl)1H-benzimidazol-2-yl]-1-piperidinyl} ethyl) phenyl]-2methylpropanoic acid tradename: Bilaxten effective in the treatment of ocular symptoms and diseases of allergies. including rhinoconjuctivitis  Bepotastine 4-[4-[(4-chlorophenyl)-pyridin2-ylmethoxy]piperidin-1-yl]butanoic acid Trade name: (Talion) ophthalmic preparation  Terfenadine .

terfenadine normally is not measurable in the plasma.(RS)-1-(4-tert-butylphenyl)-4{4-[hydroxy(diphenyl)methyl]piperidin-1-yl}-butan-1-ol brand names: Seldane in the United States. while its major active metabolite is not. is cardiotoxic at higher doses. Triludan in the United Kingdom. however. Terfenadine itself. 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. Topical:  Azelastine (RS)-4-[(4-chlorophenyl)methyl]-2(1-methylazepan-4-yl)-phthalazin-1-one . Due to its near complete metabolism by the liver immediately after leaving the gut.

Approximately 75% of an oral dose is excreted in feces. Anti-inflammatory effect. Mast-cell stabilizing effect and 3.Rhinolast in the UK. Azelastine has a rapid onset of action. Azelastine has a triple mode of action:[8] 1. and two inactive carboxylic acid metabolites. Pharmacokinetics of orally administered azelastine are not affected by age. desmethylazelastine. gender or hepatic impairment  Levocabastine (3S. and Azep in Australia. 2. Astelin/Astepro in the US.1% and 0.[10] Azelastine is oxidatively metabolized by the cytochrome P450 family into its active metabolite.15% solutions) and as eye drops (0. 15 minutes with the nasal spray[6] and 3 minutes with the eye drops. Anti-histamine effect.4R)-1-[4-cyano-4-(4fluorophenyl)cyclohexyl]-3-methyl-4-phenylpiperidine4-carboxylic acid .formulated both as a nasal spray (0.05% solution) Brand names:  nasal spray Allergodil (Europe).[9] The effect lasts for 12 hours. eye drops have been launched in over 30 countries including the UK (Optilast) and the USA (Optivar).

sinusitis. foreign body sensation. levocabastine has also subsequently been found to act as a potent and selective antagonist for the neurotensin receptor NTS2. It should not be used to treat irritation caused by contact lenses. lid edema. rhinitis. cold syndrome. a sthenia. . pruritus. dry eye.11dihydrodibenzo[b. pharyngitis.As well as acting as an antihistamine. Olopatadine {(11Z)-11-[3(dimethylamino)propylidene]-6.  Olopatadine hydrochloride 0. A nasal spray. Its side effects may include headaches (7% of occurrence) burning and stinging (5%).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). hyperemia.keratitis.1% is sold as Patanol (or Opatanol in some countries). and taste perversion. and was the first drug used to characterise the different neurotensin subtypes.

and provides relief from the typical symptoms of hay fever. but prevents it binding to its receptors. It does not prevent the actual release of histamine from mast cells. fexofenadine is associated with a decreased risk of cardiac arrhythmia compared to terfenadine. It is the R-enantiomer of the cetirizine racemate. levocetirizine is the active enantiomer of cetirizine. . This in turn prevents the release of other allergy chemicals and increased blood supply to the area. Systemic:  Levocetirizine 2-(2-{4-[(R)-(4-chlorophenyl)(phenyl)methyl]piperazin-1yl}ethoxy)acetic acid brand name: Xyzal non-sedative (does not enter the brain in significant amount). developed from the second-generation antihistamine cetirizine. Indeed.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. Levocetirizine works by blocking histamine receptors. Chemically.

[4] concluding: . It is an antagonist at histamine H1 receptors. There are no head-to-head randomised controlled trials of the two drugs. It has a long-lasting effect and in moderate and low doses. desloratadine is also effective in relieving nasal congestion. does not cause drowsiness because it does not readily enter the central nervous system.5H-benzo[5. loratadine Desloratadine is the major metabolite of loratadine. Deselex and Delot. Azomyr.[2] Unlike other antihistamines. Clarinex. Claramax.Desloratadine . 8-chloro-6. Dazit. and an antagonist at all subtypes of the muscarinic acetylcholine receptor. Desloratadine is a tricyclic antihistamine. particularly in patients with allergic rhinitis.11-dihydro-11-(4piperdinylidene).6]cyclohepta[1.2b]pyridine Trade names: NeoClarityn. which has a selective and peripheral H1-antagonist action.Larinex. Aerius. A survey of patients dissatisfied with loratadine published in August 2003 reported equal or better satisfaction with desloratadine. [3] Desloratadine vs.

and overall satisfaction (p < 0. Pharmacology The H2 antagonists are competitive antagonists of histamine at the parietal cell H2 receptor. nighttime awakening due to symptoms. a partial H2-receptor antagonist. . From this lead the receptor model was further refined and eventually led to the development of burimamide. 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.When severity of disease was controlled for in the analysis. symptom severity just prior to the next dose. They accomplish this by two mechanism: Histamine released is blocked from binding on parietal cell H2 receptors. Hundreds of modified compounds were synthesised in an effort to develop a model of the thenunknown H2 receptor. a specific competitive antagonist at the H2 receptor 100-times more potent than Nα-guanylhistamine. They suppress the normal secretion of acid by parietal cells and the meal-stimulated secretion of acid. The first breakthrough was Nαguanylhistamine.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. 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. which stimulate acid secretion. with statistically significant results reported for sum of adverse effects.

Infrequent ADRs include hypotension. and rash. To be specific. except for cimetidine. constipation. in general. tiredness. dizziness. confusion. Burimamide .General Clinical uses : H2-antagonists are used by clinicians in the treatment of acidrelated Gastrointestinal conditions. Rare ADRs include: headache. diarrhea. 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. where in all of the following adverse drug reactions (ADRs) are common. well tolerated.

1-[4-(1H-Imidazol-5-yl)butyl] -3-methylthiourea A highly specific competitive antagonist at the H2 receptor 100times more potent than Nα-guanylhistamine. but its inactive in physiological pH due to the presence of its electron donating side chain Replacement of guanidine gp with thiourea . it has H3 blocking action. 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 .

hence preserving the activity of the drug in a physiological environment.position on the imidazole ring more selectivity to H2 receptor. the addition of methyl group to the 4.1H-imidazol. Therefore replacement of the =S in the thiourea group was suggested Not used because was associated with unacceptable nephrotoxicity and agranulocytosis Cimetidine 2-cyano. .4yl)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.3-(2-[(5-methyl. It was determined that the thiourea group was the cause of the agranulocytosis. burimamide The addition of a sulfide group close to the imidazole ring.N-methyl-N'-(2-{[(4-methyl-1H-imidazol-5yl)methyl]thio}ethyl)thiourea developed from another H2 antagonist.1-methyl.

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. Cimetidine has been found to possess clinically significant antiandrogen 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.disubstitution is the best substitution pattern for the furan ring Methy substitution at C3 of furan eliminates activity whereas .1.2-nitroethene.5.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.2-yl)methylthio]ethyl)N-methyl.

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 : .

thiazole. 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. 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. 4) The imidazole ring of histamine is not required for competitive antagonism of histamine at H2-receptors.) may be used. thiophene. CH3 on C4 gives H2 selectivity . non-basic .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.substituents should be stronger electron withdrawing group for maximal antagonist activity . Other heterocyclic rings (furan. The isosteric thioether link is acceptable. 6) The terminal nitrogen group should be polar. Above structure of Na –Guanylhistamine shows first antagonist property. etc.

but probably not limited to dopamine. GABA. although there are several compounds used as research tools which are reasonably selective agonists.[1] The H3 receptor has also been shown to presynaptically inhibit the release of a number of other neurotransmitters (i. Some examples are:  (R)-α-methylhistamine . H3 receptors function as presynaptic autoreceptors on histamine-containing neurons. it acts as an inhibitory heteroreceptor) including. where they act as autoreceptors in presynaptic histaminergic neurons. and serotonin. so it leads to inhibition of the formation of cAMP.[2] Pharmacology [edit] Agonists There are currently no therapeutic products acting as selective agonists for H3 receptors. and also control histamine turnover by feedback inhibition of histamine synthesis and release. to reduce action potential mediated influx of calcium and hence reduce neurotransmitter release. The H3 receptor is coupled to the Gi G-protein. Also.Histamine H3 receptors are expressed in the central nervous system and to a lesser extent the peripheral nervous system.e. acetylcholine. Function Like all histamine receptors the H3 receptor is a G-protein coupled receptor. the β and γ subunits interact with N-type voltage gated calcium channels. noradrenaline.

  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 .

monocytes. liver. It is also expressed in the colon. Function They have been shown to mediate mast cell chemotaxis. mast cells. The H3 receptor antagonist clobenpropit also binds with high affinity to the H4 receptor but also possesses weak H4 agonist activity . small intestine. High affinity h3 agonist 4 methyhistamine has H4 agonist properties although their relative potency with respect to histamine is generally lower . Shows preferential distribution in cells of immunological relevance such as seems to do this by the mechanism of Gi-coupled decrease incAMP. and trachea. During the search for histamine H4-receptor ligands. spleen.H4 is expressed primarily in the bone marrow and eosinophils. thymus. and regulates neutrophil release from bone marrow. It was clear that there is considerable overlap in the pharmacology of h3 and H4 receptor. tonsils. lung. Structure The 3D structure of the H4 receptor has not been solved yet due to the difficulties of GPCR ( G protein-coupled receptor )crystallization. testes. 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. 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 . . .

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-1carbothioamide Capable of crossing the blood–brain barrier.     .

VUF-6002 5-Chloro-2-[(4-methylpiperazin-1-yl)carbonyl]-1Hbenzimidazole Orally active and inhibits the activity of both mast cells and eosinophils in vivo. and has been demonstrated to be superior to traditional antihistamines in the treatment of pruritus (itching). . 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 . . A potential H4 antagonist drug is currently being tested in a phase II clinical trial. and has antiinflammatory. It has antiinflammatory effects.