Chapter 3.4

Antihistamines

Histamine H1 AntagonistsThe term antihistamine historically refers to drugs that antagonize the actions of histamine at H1 receptors.

Histamine is an important chemical mediator of hypersensitivity

4 (5-)-(2-aminoethyl)imidazole

4(5)-(2-aminoethyl) imidazole(a) N-tautomer (a) N-tautomerSide chain N = N

At pH 7.4, histamine exists almost exclusively (96.6%) in a monocationic form

Most histamine is synthesized and stored in mast cells and basophilic granulocytes

Histamine is mediated by specific cell surface receptors (H1, H2, and H3)Properties and Action of Histamine

Biosynthesis and metabolism of histaminehistidinehistidine decarboxylasehistamineN-methyltransferaseMAO (brain)DAO (peripheral)Aldehyde dehydorgenaseN-methyl histamineimidazolyl acetic acidMAO (brain)DAO (peripheral)Aldehyde dehydorgenaseribose phosphatetransferase N-methylimidazolyl acetic acidImidazolyl acetic acidnecleoside

Classification of H1 receptor antagonists lipophilic aromatic moietydiaminespiperazinesaminoethersPropylaminePiperdinestricyclics

Histamine H1 Receptor Antagonists ethyl diaminesaminoetherspropylamineschlorphenamine maleate tricyclicsloratadine piperazinescetirizine hydrochloride piperidinesmizolastine others

Ethyl diamines H1 receptor antagonistsAr = Php-subPh or thtiophenylAr= Ph or 2-pyridinylR and R = Me or heterocyclyl

Weaker action to H1 receptormoderate central analgesic effectcausing disorder of gastrointestine local external use may cause skin hypersensity.

Aminoethers H1 receptor antagonistsIf ArArCHO- replace ArCH2ArN- moiety in ethyl diamines, then you get aminoethers.

The first generation of H1 receptor antagonist display apparent analgesic and anticholinergic effectsusually with side reaction like somnolence, dizzy, oral dryness. But incidence rate of gastrointestine reaction is low. Some of drugs could be applied in the treatment of insomnia.For those aminoether with two aromatic groupthe activity of S-isomer is usually higher than that of R-isomer.

Antihistamine drugs without analgesic effect belonged to aminoether typethey have higher selectivity to peripheral H1 receptor, belong to second generation antihistamine drug. ClemastineSetastine Aminoethers H1 receptor antagonists

Propylamines H1 receptor antagonistsWhen ArCH2(Ar)N- in ethyldiamines is replaced by Ar(Ar)CH- moietyor omitted -O- in aminoether, then propylamine is there.

Compared to traditional antihistamines like ethyldiamines, aminoethers, tricyclicspropylamines have stronger antihistamine action but weaker central analgesic, and less tendency of inducing somnolence.

Chlorphenamine is an first-generation antihistaminesChlorphenamine Maleate

Action of Chlorphenamine Maleate Stronger antihistamine actionless dosageless side effectsuitable for children. Mainly use for hypersensitive nasitis, skin mucosa hypersensitivity, urticaria, angiectatic nasitis, hay fevercontact dermatitis and hypersensitivity caused by food and drugs. Side effect: somnolence, thirsty, diuresis.

Points Need Your ConcernsOne chiral center in Chlorphenaminethere is a pair of optical isomer. The activity of S-isomer is twice stronger than that of racemateacute toxicity is also less. The activity of R-isomer is only 1/90 than that of racemateIn clinic, racemate chlorphenamine maleate is used

Chemical Synthesis

Propylamines H1 receptor antagonistsAllyl acid make the compound more hydrophilic and it is more difficult for it to enter into central nerve system.Therefore, acrivastine displays no analgesic effect.The activity of E-isomer is great higher than that of Z-isomer.Acrivastine

Tricyclics H1 receptor antagonistsIf fused together the adjacent position of two aromatic ring, tricyclics H1 receptor antagonist is there.

If X = NY = Sthen phenothiazine If X= C (sp2)Y is replaced with bioisostere, -CH=CH-then cyproheptadine Further modification of cyproheptadine produce loratadine

Loratadine Strong selective H1 receptor antagonist, but no anticholinergic activity and central nerve system inhibition, belong to second generation non-sedative antihistamines. The main difference compared to other tricyclics antihistamines, is the replacement of neutral aminoformate for basic tertiary amine. It is believed this is the reason of its decrease of central analgesic .

Chemical Synthesis of Loratadine

Piperazines H1 Receptor AntagonistsWhen ArArCHN- replaces ArCH2ArN- moiety in ethyldiamine, and make two nitrogen atom in piperazine ring, then the piperazines antihistamines are constructed

Other than stronger H1 receptor antagonism effectthey display other characteristiclike relieving asthma effect, anti-kinetia action, and blocking action of Ca2+ ion channel .

Cetirizine Hydrochloride Because of the easy ionization of Cetirizine, the drug is not easy to permeate blood brain barrier (BBB) , little amount of the drug is able to arrive central nerve system, it belongs to non-sedative antihistamine, it is one of the representative drug of second generation antihistamines.

The advantages of Zyrtec is that

Once-daily dosing

Rapid onset of activity (20-60 min)

Minimal CNS effects

Process for Synthesizing Cetirizine Hydrochloride

Piperidines H1 Receptor AntagonistsLimitation of the entrance to central and increase the selectivity to H1 receptor, is the guiding ideology for design and searchin new antihistamine drugs. This resulted in the development of non-sedative H1 receptor antagonists.ClemastineaminoethersAcrivastinepropylaminesLoratadinetricyclics, and Cetirizinepiperazinesall belong to non-sedative H1-receptor antihistamines. Via the introduction of hydrophilic group, the drug is difficult to enter central nerve system because of BBB, therefore the sedative effect is overcome (weakened). Whilst Clemastine and Loratadine have higher selectivity to peripheral H1 receptor, therefore avoid side effect to Centrum. Other non-sedative antihistamine drugs belong to piperidines selective peripheral H1-receptor antagonists.

Mizolastine 2-[[1-[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]-4-piperidinyl]methylamino]-4(1H)-pyrimidinone2-1-1-4--1H--2--4--43H-

Process for Synthesizing Mizolastine

SAR of Antihistamines X = O, C, or N

N = 2 or 3lipophilic aromatic moietydiaminespiperazinesaminoethersPropylaminePiperdinestricyclics