Histamine and Antihistaminic Agents

HISTAMINE AND ANTIHISTAMINIC AGENTS

Dr. Mervat El-Hamamsy Tanta University Histamine is a physiologically active, endogenous substance that is produced within the body by the decarboxylation of the amino acid, histidine, and stored in mast cells and basophils where it is protected from destructive enzymes, such as histaminase. It binds to and activates histamine H1 – and H2 – receptors in various sites in the body. H3 – receptors, which may be involved in the control of histamine synthesis, also have been described. 2 HISTAMINE BIOSYNTHESIS

NH NH2 2

COOH H H H Histidine Decarboxylase N N N N H Pyridoxal Phosphate H

Histamine Biosynthesis

 Nomenclature Histamine, 4-(2-aminoethyl) imidazole. The methylene groups of the amino-ethyl side chain are designated α and β. The side chain is attached, via the β-CH2 group, to the 4 position of an imidazole 3 ring. STEREOCHEMISTRY

Histamine is achiral molecule; the influence of conformational isomerism on activity of histamine suggest the importance of trans – gauch rotameric structures. 4 FUNCTIONS OF ENDOGENOUS HISTAMINE Histamine exhibits a wide variety of both physiological and pathological function in different tissues and cells. (a) a chemical mediator of hyper – sensitivity reactions, (b) regulation of gastric acid secretion, (c) a neurotransmitter in the CNS.

5 HISTAMINE 1 ANTAGONISTS (ANTIHISTAMINE AGENTS(

The term antihistamine historically has referred to drugs that antagonize the actions of histamine at H1 receptors rather than H2 receptors. H1 antagonists may be defined as drugs that competitively inhibit the action of histamine on tissues containing H1 receptors.

6 STRUCTURE – ACTIVITY RELATIONSHIPS The H1 antagonists are subdivided into two broad groups : the first generation, or classical, antihistamines and the second generation, or ' nonsedating, antihistamines. The SAR analysis for H1 antagonists for the first generation agents.

7 STRUCTURE – ACTIVITY RELATIONSHIPS Ar R

X (CH2)n N Ar' R' General antihistamine structure

1. Ar is aryl ( including pheny1, substituted pheny1, and heteroary1 groups such as 2- pyridy1); 2. Ar' is a second ary1 or arylmethy1 group 3. X is a connecting atom of O, C, or N 4. (CH2)n represents a carbon chain. Usually ethy1;

5. NRR’ represents a basic, terminal amine function.8 FIRST GENERATION H1- ANTAGONIST DRUG CLASSES

R'' R Ar' CH N O CH2 2 Ar R' General structure of the amino alkyl ethers 1. Amino Alkyl Ethers (Ethanolamines)  The aminoalkyl ether antihistamines are characterized by the presence of CHO connecting moiety (X) and a two –or three –carbon atom chain as the linking moiety between the key diary and tertiary amino groups.  Replacement of one of the phenyl rings of the diphenhy

diamine with a 2- pyridyl group as in doxylamine and 9 carbinoxamine, enhances antihistaminic activity. DIPHENHYDRAMINE HYDROCHLORIDE 2-(DIPHENYLMETHOXY)-N,N-DIMETHYL ETHANAMINE HYDROCHLORIDE (BENADRYL)

In addition to antihistaminic action, diphenhydramine exhibits antidyskinetic, antiemetic, antitussive, and sedative

10 SYNTHESIS

 By heating diphenyl bromomethane, β-dimethylaminoethanol and sodium carbonate in toluene. Diphenhydramine is converted to the hydrochloride with hydrogen chloride.

11 BROMODIPHENHYDRAMINE

 Bromodiphenhydramine is 2[(4-bromophenyl) phenylmethoxy)]-N, N-dimethylethanamine Synthesis:

12 DIMENHYDRINATE, (IDENT) 8-CHLOROTHEOPHYLLINE 2- (DIPHENYLMETHOXY)-N,N- DIMETHYLETHYLAMINE (DRAMAMINE) .

 Dimenhydrinate is recommended for the nausea &vomiting of motion sickness and pregnancy.  A salt of two drugs: diphenhydramine and 8- chlorotheophylline.

_ O

N NCH3 CHOCH2CH2NH(CH3)2 + Cl N N O 13

Dimenhydrinate CH3 2. ETHYLENEDIAMINES Ar R

N CH2 CH2 N Ar' R' General structure of ethylediamines

 They are characterized by the presence of a nitrogen connecting atom (X) and a two carbon atom chain as the lining moiety between the key diary and tertiary amino moieties.  All compounds in this series are simple diarylethylenediamines except antazoline in which the terminal amine and a portion of the carbon chain are 14 included as part of an imidazoline ring system. ANTAZOLINE PHOSPHATE

2-[(N-benzylanilion)methyl]-2-imidazoline dihydrogen phosphate. Antazoline less active than most of the other antihistaminie drugs, but it is characterized by the lack of local irritation. The more soluble phosphate salt is applied topically to the eye in a 0.5% solution. The less soluble hydrochloride is given orally. Antazoline has more than twice the local anesthetic 15 potency of procaine and exhibits anticholinergic actions. PIPERAZINES (CYCLIZINES)

 The piperazines or cyclizines can also be considered ethylenediamine derivatives or cyclic ethylenediamines (cyclizines);  in this series, the connecting moiety (X) is CHN group, and the carbon chain, terminal amine functionality, and the nitrogen atom of the connecting group are all part of a piperazine 16 moiety. CHLOROCYCLIZINE

is a piperazine derivative. It is 1-(p- chlorobenzhydryl)- 4-methylpiperazine. The antihistaminic activity of piperazines is reduced if halogen is introduced at 2 or 3 position of 17 phenylring ring structures. SYNTHESIS.

 Chlorcyclizine is prepared by condensation of p- chlorobenzhydryl chloride with N-methylpiperazine.

18 3. PROPYLAMINES (MONOAMINOPROPYL DERIVATIVES)

Ar R

CH CH2 CH2 N Ar' R' General structure of the propylamines

 The propylamine antihistamines are characterized structurally by sp3 or sp2 carbon connecting atom with a carbon chain of two additional carbons linking the key tertiary amino and diaryl pharmacophore moieties. Those propylamines with a saturated carbon connecting moiety are commonly referred to as the pheniramines. All of the pheniramines 19 consist of a phenyl and a 2-pyridyl aryl group and a terminal dimethylamino moiety. CHLORPHENIRAMINE MALEATE; Cl

N CHCOOH C CH2CH2N(CH3)2 H CHCOOH Chlorpheniramine Maleate Dexchlorpheniramine Maleate 2[α-[2- dimethylaminoethyl] benzyl] pyridine. This drug is is marketed as the racemate

20 TRIPROLIDINE

21 4. PHENOTHIAZINE

 The phenothiazine derivatives that display therapeutically useful antihistaminic actions a two-or three-carbon branched alkyl chain between the ring system and terminal nitrogen  Phenothiazines with a three carbon bridge between nitrogen atoms are more potent.  The heterocyclic ring of the antihistamines is unsubstituted. 22 PROMETHAZINE HYDROCHLORIDE

 10-[2-(dimethyamino)propyl]phenothiazine monohydrochloride (phenergan)

CH2CHN(CH3)2 . HCl

CH3 Promethazine HCl

23 5. DIBENZOCYCLOHEPTENES AND DIBENZOCYCLOHEPTANES

HCl N

CH3 Cyproheptadine HCl  The dibenzocycloheptene and dibenzocycloheptane antihistamines may be regarded as phenothiazine analogues in which the sulfur atom has been replaced by an isosteric vinyl group (cyproheptadine) or a saturated ethyl bridge (azatadine), 24  the ring nitrogen has been replaced by an sp2 carbon atom . CYPROHEPTADINE HYDROCHLORIDE,

HCl N

CH3 Cyproheptadine HCl

Cyproheptadine possesses both antihistamine and antiserotonin activity and is used as an antipruritic agent. 25 AZATADINE

Is a potent, long –acting antihistaminic with antiserotonin – activity.

26 SECOND-GENERATION H1- ANTAGONIST DRUGS The second-generation antihistamines are more similar pharmacologically than structurally. The second-generation agents have little affinity for muscarinic, adrenergic or serotonergic receptors and therefore display a lower incidence of side effects associated with antagonism at these receptors 27 FEXOFENADINE HYDROCHLORIDE (IDENT)

 (+,-)-4- [1-hydroxy -4-[4-(hydroxydiphenylmethy] 1- piperinyl]butyl-α,α-dimethylbenzene acetic acid  Fexofenadine is a primary oxidative metabolite of terfenadine. 28 LORATADINE,

COOC2H5 Loratadine 4-(8-chloro-5,6 –dihydro-11H-benzo[5,6]-cyclohepta[1,2- b]pyridine-ll-ylidenel-carboxylic acid ethyl ester. Loratadine is structurally related to the antihistamines azatadine and cyproheptadine. It differs from azatadine, in that a neutral carbamate group has replaced the basic tertiary amino moiety, and a phenyl 29 ring has been substituted with a chlorine atom. INHIBITION OF HISTAMINE RELEASE: MAST CELL STABILIZERS

The discovery of the bronchodilating activity of the natural product Khellin led to the development of the bis (chromones) as compounds that stabilize mast cells and inhibit the release of histamine and other mediators of this class was  cromolyn sodium and nedocromil.

30 MAST CELL STABILIZERS (IDENT)

Na OOC O O COO Na

O O OCH2CHCH2O

OH Cromolyn Sodium

 are cromone medications used to prevent or control certain allergic disorders.  They block a calcium channel essential for mast cell degranulation, stabilizing the cell and thereby preventing the release of histamine and related

mediators. One suspected pharmacodynamic mechanism31 is the blocking of IgE-regulated calcium channels. PEMIROLAST POTASSIUM

It can be considered an analogue of one portion of the cromolyn structure in which the carboxy group has been replaced with an isosteric tetrazole

moiety. 32 RECENT ANTIHISTAMINE DEVELOPMENTS: THE DUAL-ACTING ANTIHISTAMINCS

HOOC H

H COOH N Ketotifen Fumarate

CH3

 dual mechanisms of action including H1-receptor antagonism and mast cell stabilization.  Currently available drugs include azelastine and ketotifen these compounds contain the basic pharmacophore to produce relatively selective histamine H1 antagonism (diarylakylamines) as inhibition of the release of histamine and other mediators leukotrienes 33 from mast cells involved in the allergic response.