الله بسمالرحمن الرحيم

Antihistaminic drugs

Histamine

Histamine is an autacoid i.e physiologically active, endogenous

substance that is produced within the body by decarboxylation of

the amino acid Histidine and then stored in mast cells and

basophils. It is released in response to a wide variety of stimuli

mediating a hypersensitivity reaction. Histamine action is

terminated by cellular reuptake and enzymatic inactivation.

NHN

NH2

Tautomers of HistamineNHN

NH2

N tautomer

N tautomer

Biosynthesis of histamine

NHN

NH2

NHN

NH2

COOH

Histidine Histamine

Nomenclature

NHN

NH2

1

2

45

3 NHN

NH2

3

2

54

1 4(5)(2-aminoethyl)1H imidazole

Histamine Receptorsor physiological effects

of histamine

1. H1–receptors : Has a role in hypersensitivity reactions

[Pruritis , Increased vascular permeability (oedema, swelling),

Increased prostaglandin generation] and also Mediate smooth

muscle contraction.

2. H2–receptors : mediate the gastric acid secretion as they are

located on the cell membrane of acid secretory cells of the

gastric mucosa

3. H3 – receptor : described in 1999 , modulate histamine

synthesis and release in the CNS.

N.B. H4 subtype is recently discovered in 2000 and was suggested

to have a role in regulation of immune system.

Histamine exhibits a wide variety of both

physiologic and pathologic functions and this include:

1- An important but limited role as a chemical

mediator of hypersensitivity reactions.

2- A major role in the regulation of gastric acid

secretion.

3- A role as a neurotransmitter in the CNS.

Histamine has no therapeutic application.

The compound is mainly used as

1- a positive control in the allergy skin

testing.

2- a diagnostic agent to test the secretory

action of the stomach.

Histamine H1- Receptor

Antagonists

Histamine H1- Receptor Antagonists

• H1- antagonists are the drugs that competitively

inhibit the action of histamine on the tissues

containing H1-Receptors.

H1 receptor

Drug

Drug

histamine No reaction

Competitive inhibition

H1 receptor

• The H1-antagonists are commonly subdivided into two

broad groups:

The first generation or classical

antihistamines (sedating)

The second generation or (non sedating)

antihistamines.

Structure Activity Relationship (S A R) of the first generation antihistamines

(CH2)nX N

R

R-

Ar

-Ar

Connecting atom C.chainTerminal nitrogen or tertiary amino moiety

1 -connecting atom X

X= C O

X= C

X= N

C O CH2CH2 N

Aminoalkyl ether or ethanolamine dr.

C CH2CH2 N

C CHCH2 N

Propylamine dr.

N CH2CH2 N

Ethylenediamine dr.

(CH2)nX N

R

R-

Ar

-Ar

2- The carbon chain of typical H1–antagonists consists of

two or three carbon atoms.

3- The terminal nitrogen atom is a simple dimethyl amino

moiety. However, it may be a part of a heterocyclic

structure as in (piperazine, pyrrolidine , piperidine,

imidazole…….).

N

H3C

NTriprolidine

X

4- Ar and Ar` are aryl groups, including phenyl, substituted

phenyl (specially with halogen in para position) and

heteroaryl such as 2-pyridly. The two aryl moieties must be

non coplanar to each other for optimal interaction with H1

receptor. The two aromatic systems may be linked as in

the tricyclic antihistamines.

1- They have high lipid solubility so, they can penetrate BBB blocking central H1 receptors and some CNS

receptors. Sedation, dizziness.

2- They contain the basic pharmacophore required for binding to muscarinic as well as adrenergic and serotonergic receptors overlaping actions different pharmacological actions.

*****

Characters of first generation antihistamines

A- Amino alkyl Ethers (Ethanolamines).

-Ar C

R--

Ar

H2C

H2C N

R-

R

O

1 -Diphenhydramine HCl (Benadryl)

• It is used in the treatment of urticaria, seasonal

rhinitis, and some dermatoses.***

• It is used as a sleep aid product. ***

2-(Diphenylmethoxy)-N,N dimethylethylamine HCl

CH O CH2CH2 NCH3

CH32 1

HCl

Synthesis

CH O CH2CH2 NCH3

CH32 1

HCl

Br

HON

CH3

CH3

Na2CO3

Metabolism

Question?

CH O CH2CH2 NCH3

CH3

HCl

B- Propylamine derivatives 1- Saturated dr. (pheneramines)

2- Unsaturated dr. (Olefinic) open chain dr. Cyclic analogues

CH2CH2 N

R-

R

CH

Ar

-Ar

1 -saturated dr. A- chlorpheniramine Maleate

• Insertion of a halogen into the para position of the

phenyl ring increases potency and duration. D optical

isomer with S absolute configuration is more active

( dexchlorpheneramine maleate)

2-[ p-chloro-α-[ 2-dimethylaminoethyl ] benzyl] pyridine maleate.

CH

N

CH2CH2 NCH3

CH31 2CHCOOH

CHCOOH

Cl

1

2

.

2 -unsaturated dr. A- open chain dr.

Triprolidine Hydrochloride

E (trans geometric isomer in which the methylpyrolidinyl group is

trans to the 2- pyridyl group) is more active than the Z (cis)

isomer.

• N.B. adding polar group……..as 2-propenoic acid ……second

generation (acrivastine).

(E)-2- [ 1-(4-methylphenyl)3-(1-Pyrrolidinyl) 1-propenyl] pyridine.

N

H

Cl-

H3C

N

1 2

3

1

2

B- Cyclic analogue Dimethindene maleate (fenistil)

The potent antihistaminic activity resides mainly in the

levorotatory isomer.

2- [ 1-[2-(2-dimethylamino) ethyl] indene-3-yl]ethyl]] pyridine maleate.

1

2CHCOOH

CHCOOH

1

2

.

CH

CH2CH2 NCH3

CH31 2

H3C N2

31

c- Ethylenediamines The earliest series of H1-antagonists

Characterized by high CNS side effects and lower anticholinergic and antiemetic effects

N CH2CH2 N

R-

R

-Ar

Ar

E-Tricyclic ring system1-Phenothiazine

2- phenothiazine analogues (Cycloheptane and cycloheptene dr.)

N

CH2CH(CH2)n N

R2

R1

R

S

1 -Promethazine HCl [ phenergan]

It is the parent member of this series .

It forms HCl salt with the more basic nitrogen ?

In addition to its antihistaminic action, it has antiemetic, anticholinergic and sedating effects

It forms HCl salt with the more basic nitrogen?

(±)10-[2-(Dimethylamino)propyl ] phenothiazine.

N

S

CH2CH

CH3

NCH3

CH3

1

2

4

3

9 87

6

5

10

12

3

Preparation of Promethazine HCl

N

H

S

FusionN

S

H

ClH2C

HC N

CH3 CH3

CH3NaNH 2

/Toluene

-HCl

Promethazine

Phenothiazine analogues 1-Pimethixene

S5

6

8

7

10 43

2

1

9

N

CH3

1-methyl-4-[ 9H-thioxanthen-9-ylidene]piperidine

1

4

1- It is an example for thioxanthene derivatives as potent H1

antagonist. 2- It is an example for the bioisosteric replacement

of the nitrogen of phenothiazine nucleus by an SP2 carbon atom.

2 -Cyproheptadine HCl (periactin)

• It is an example for the bioisosteric replacement of the nitrogen of phenothiazine nucleus by an SP2 carbon atom and the sulphur atom is replaced by an isosteric vinyl group.

• This compound can be used as an appetite stimulant and it exhibits both H1-antagonist and antiserotonergic activity.

4-(5H-Dibenzo [a,d] cyclohepten-5-ylidene)-1-

methylpiperidineN

1

2

34

5

1

4

H3C

ab c

d

S

N

CH3

pimethixene

N

H3C

Cyproheptadine

N

N

CH3

Azatidine

N

S

CH2CH

CH3

NCH3

CH3

Promethazine

1- It is structurally analogous to cyproheptadine.

2- It is a dual acting antihistaminic which acts as potent H1-antagonist and and mast cell stabilizer (it inhibits the release of the mediators which are involved in the allergic reaction)

3- It is used in prophylaxis of asthma

N

CH3

O

S

Ketotifen (Zaditine)