Histamine is a chemical messenger which are synthesized in the mast cell. Histamine is present in practically all tissues , with significant amounts in the lungs, skin, blood vessels and GI tract. Generally histamine are found in the animal tissue , venom of insects bacteria and plant. Histamine a substance that play a major role in many allergic reaction , dilating blood vessel and making the vessel walls abnormally permeable. Histamine is a signalling molecule ,sending message b/w cells. It tells stomach cells to make stomach acid and it helps our brain English scientists George Barger and Henry H. Dale first isolated histamine from the plant fungus ergot in 1910 and in 1911 they isolated the substance from animal tissues. Histamine [2 (imidazole -4-yl) ethylamine] which is biosynthesized by decarboxylation of the basic amino acid histidine ,is found all organ and tissue of the human body. It is formed by the decarboxylation (the removal of a carboxyl group) of the amino acid histidine. These are the drugs which diminish or antagonize the action of endogenously released histamine in the body . Antihistamines are generally antagonist of H1 receptor. These are used for the treatment of allergy and pruritis Antagonist of H2 receptor are use to inhibit gastric acid secretion (treatment of peptic ulcer). The human body contains histaminic receptor and are divided into three different types upon their action H1- receptor H2- receptor H3- receptor In the year 1933 the first drug Piperoxan invented Bovet & Furnease. This drug can protect the animal from bronchial spasm. The drug is the initiation for the discovery of H1 receptor antagonist. In the year 1942 , Halpen researched and reported about 24 derivative of ethylene diamine in which Phenbenzamine was found to be most potent and is used the first H1 antagonist used clinically. H1 antagonists act by competitively inhibiting the effects of histamine at H1 receptor SAR –H1 RECEPTOR ANTAGONISTS 1st Generation Antihistaminic agents PROYLAMINE ANALOGS It is most potent antihistaminic agents. The activity is mainly due to geometric isomer in which the pyrrolidino - methyl group is trans to the 2pyridyl group. E isomer showed more activity then Z isomer. The histamine H2 receptor antagonist act on H2 receptor in the stomach blood vessel and other sites. They are competitive antagonist of histamine and are fully reversible H2 antagonist are group of medicines that reduce the amount of acid produced by the cell in the lining of the stomach are commonly called H2 blocker These products have been approved for the relief of “heartburn” associated with acid indigestion ,and sour stomach. Drugs – cimetidine, ranitidine, famotidine. SAR OF H2 ANTAGONIST Other Heterocyclic ring present like Cimetidine ( Imidazole) ,ranitidine (furan), famotidine (Thiazole) etc ,that enhance the potency and selectivity of H2 receptor antagonist can be used. The ring is terminal nitrogen should be separated by four carb

1. H1 and H2 antagonist
By- Aniket kumar
M. Pharm 1st semester
(pharmaceutical chemistry)

2. CONTENTS
HISTAMINE
ANTIHISTAMINE
RECEPTOR OF ANTIHISTAMINE
CLASSIFICATION OF H1 ANTIHISTAMINE
MOA H1 ANTAGONIST
SAR OF H1 ANTAGONIST
H2 ANTAGONIST
MOA H2 ANTAGONIST
SAR OF H2 ANTAGONIST

3. Histamine
• Histamine is a chemical messenger which are synthesized in the mast cell.
• Histamine is present in practically all tissues , with significant amounts in
the lungs, skin, blood vessels and GI tract.
• Generally histamine are found in the animal tissue , venom of insects
bacteria and plant.
• Histamine a substance that play a major role in many allergic reaction ,
dilating blood vessel and making the vessel walls abnormally permeable.
• Histamine is a signalling molecule ,sending message b/w cells. It tells
stomach cells to make stomach acid and it helps our brain

4. • English scientists George Barger and Henry H. Dale first isolated histamine
from the plant fungus ergot in 1910 and in 1911 they isolated the substance
from animal tissues.
• Histamine [2 (imidazole -4-yl) ethylamine] which is biosynthesized by
decarboxylation of the basic amino acid histidine ,is found all organ and tissue
of the human body.
• It is formed by the decarboxylation (the removal of a carboxyl group) of the
amino acid histidine.

5. ANTIHISTAMINE
• These are the drugs which diminish or antagonize the action of
endogenously released histamine in the body .
• Antihistamines are generally antagonist of H1 receptor.
• These are used for the treatment of allergy and pruritis
• Antagonist of H2 receptor are use to inhibit gastric acid secretion (treatment
of peptic ulcer).
• The human body contains histaminic receptor and are divided into three
different types upon their action
1. H1- receptor
2. H2- receptor
3. H3- receptor

6. Name of receptor Place where it present in our
body
Antagonist
H1-receprtor
Smooth muscles ,intestine , bronchi , blood
vessels
Diphenhydramine
mepyramine
H2-receptor Gastric parietal cells Cimetidine
ranitidine
H3 –receptor Neuron , CNS cells Thioperamide
RECEPTORS OF ANTIHISTAMINES

7. H1 RECEPTOR ANTAGONIST
• In the year 1933 the first drug Piperoxan invented Bovet & Furnease. This
drug can protect the animal from bronchial spasm. The drug is the initiation
for the discovery of H1 receptor antagonist.
• In the year 1942 , Halpen researched and reported about 24 derivative of
ethylene diamine in which Phenbenzamine was found to be most potent and
is used the first H1 antagonist used clinically.
• H1 antagonists act by competitively inhibiting the effects of histamine at H1
receptor

9. Mechanism of action of H1 antagonist
H1 antagonist

10. • CLASSIFICATION OF H1 ANTAGONIST
H1 ANTAGONIST
FIRST GENERATION
1. AMINO ALKYL ETHERS - DIPHENHYDRAMINE
2. ETHYLENEDIAMINE – TRIPELENNAMINE
3.CYCLIC BASIC CHAIN DERIVATIVE-
CHLORCYCLIZINE
4.PROPYL AMINE DERIVATIVE- PHENIRAMINE,
TRIOLIDINE
5.PHENOTHIAZINE DERIVATIVE- PROMETHAZINE
6. DIBENZO CYCLOHEPTADINE- AZATIDINE
7. MISSCELLANEOUS - ANTAZOLINE
SECOND GENERATION
1.PIPERAZINE-
CETRIZINE/LEVOCETIRIZINE
2.PIPERIDINES- FEXOFENADINE ,
LORATADINE/ DESLORATADINE

11. SAR –H1 RECEPTOR ANTAGONISTS
1. Aryl groups
The diaryl substitution is essential for significant H1 affinity. It is present both in first
generation and second generation antihistamines. The optimal antihistaminic activity
depends on the co-planarity of two aryl substitutions.
Active aryl substitutions are as follows:
Ar1 is phenyl and hetero aryl group like 2-pyridyl Ar1 -Aryl or aryl methyl group

12. 2. Nature of X
Antihistamines with X = carbon (pheniramine series) represents the stereo selective receptor
binding to the receptors due to its chirality.
The active substitutions of X are as follows:
Where X = oxygen (amino alkyl ether analogue)
X = nitrogen (ethylene-diamine derivative)
X = carbon (mono amino propyl analogue)
3. The Alkyl Chain
Most of the antihistamines have ethylene chain, and branching of this chain results in a less
active compound.

13. 4. Terminal nitrogen atom:
The terminal N-atom should be a 3° amine for maximum activity. The terminal nitrogen
may be a part of heterocyclic ring. For example, antazoline and chlorcyclizine, retains high
antihistaminic activity. The amino moiety deserves the protonation on interaction with H1
receptor due to the basicity with pka 8.5-10
chlorcyclizine

14. 1st Generation Antihistaminic agents
AMINO ALKYL ETHERS
DIPHENHYDRAMINE
DOXYLAMINE
USES- Antiemetic,
Antihistamine, Antitussive
,smooth , Muscle Relaxant ,
sedative Action
USES- Cough ,cold ,
allergic conjuctivites

15. ETHYLENDIAMINE DERIVATIVE
Tripelennamine
USES- Allergic rhinitis ,
Conjunctivitis, Angioedema
Uses-Urticaria, conjunctivitis ,hay fever ,antiemetics
CYCLIC BASIC CHAIN DERIVATIVE
Cyclizine Chlorcyclizine

16. PROYLAMINE ANALOGS
Triprolidine
• It is most potent antihistaminic
agents.
• The activity is mainly due to
geometric isomer in which the
pyrrolidino - methyl group is
trans to the 2pyridyl group.
• E isomer showed more activity
then Z isomer.

17. PHENOTHIAZINE DERIVATIVE-
PROMETHAZINE
• It is the most potent
antihistaminic agents
• Use in perennial and
seasonal allergic rhinitis,
allergic conjunctivitis
USES-

18. 2nd Generation Antihistaminic agents
Fexofenatidine
• Used in the
treatment of
allergy
symptoms, such
as hay fever ,
watery eyes,
runny nose,
itching eyes
,sneezing, and
urticaria
• Sedative
peripheral h1
blocker
Loratidine
It is long acting ,non sedative tricyclic
antihistaminic drug.
Used to treat sneezing , runny nose,
watery eye, skin rash , itching, and
cold or allergy symptoms

19. SYNTHESIS OF CETIRIZINE

20. H2 Antagonist
• The histamine H2 receptor antagonist act on H2 receptor in the stomach
blood vessel and other sites.
• They are competitive antagonist of histamine and are fully reversible
• H2 antagonist are group of medicines that reduce the amount of acid
produced by the cell in the lining of the stomach are commonly called
H2 blocker
• These products have been approved for the relief of “heartburn”
associated with acid indigestion ,and sour stomach.
• Drugs – cimetidine, ranitidine, famotidine.

22. H2 antagonist
MECHANISM OF ACTION H2 ANTAGONIST

23. SAR OF H2 ANTAGONIST
• The H2 receptor antagonist were the result of the intentional
modification of the histamine structure and deliberate search for a
chemically related substance that would act as a competitive inhibitor.
Imidazole ring is not the only required ring fir competitive antagonism of
histamine H2 receptor

24. • Other Heterocyclic ring present like Cimetidine ( Imidazole) ,ranitidine
(furan), famotidine (Thiazole) etc ,that enhance the potency and
selectivity of H2 receptor antagonist can be used.
• The ring is terminal nitrogen should be separated by four carbon atom
for optimum antagonistic activity.
• The terminal nitrogen group should be polar ,non basic substituent for
maximal antagonistic activity.

25. H2 receptor antagonist
Cimetidine
Famotidine
Cimetidine is a stomach acid reflux that is
used to treat and prevent certain types of
stomach ulcer
Used to treat gastroesophageal reflux
disease (GERD) and heart burn.
Famotidine is used to treat and
prevent ulcers in the stomach and
intestine.
It is used to trat Zollinger- Elison
syndrome

26. RANITIDINE
USES-
• In the treatment and prevention of stomach and intestinal ulcers
• In the treatment of gastritis (stomach inflammation) caused by kidney failure
• Used is in the management of acid reflux disease to reduce injury to the oesophagus
( food tube) caused by the upward movement of stomach acid.

27. REFFERENCES
• Eliezer J. Barreiro, Arthur E. Kümmerle, and Carlos A. M. Frag . The
Methylation Effect in Medicinal Chemistry. Chemical Reviews 2011,
111 (9) , 5215-5246
• . A. M. Mocking, R. Bosma , S. N. Rahman, E. W. E. Verweij, Daniel A.
McNaught-Flores, Henry F. Vischer , Rob Leurs . Molecular Aspects of
Histamine Receptors.
• Patrick Igel , Stefan Dove, Armin Buschauer . Histamine H4 receptor
agonists. Bioorganic & Medicinal Chemistry Letters 2010, 20 (24) ,
7191-7199.