- Histamine was first identified in 1911 and is found throughout the human body. It is synthesized from the amino acid histidine and stored in mast cell granules. - Histamine binds to four receptor types (H1, H2, H3, H4) and is involved in various physiological processes like smooth muscle contraction and vasodilation. It causes allergic symptoms. - Antihistamines work by blocking H1 and/or H2 receptors. First generation antihistamines are sedating while second generation ones are non-sedating. Structural requirements for antihistamine activity include diaryl substitutions, an optimal distance between rings, and a tertiary amine group.

1. chemistryguru10@gmail.com
Surendra Kumar
Assistant Professor (M. Pharm)
KNIMT, Faculty of Pharmacy, Sultanpur
BP501T

2.  Histamine was first identified in 1911 by Barger and Dale. Anti-histamines are
the drugs which counteract the actions of histamine in the body.
 Histamine [2-(imidazol-4-yl) ethylamine], which is biosynthesized by
decarboxylation of the basic amino acid histidine, is found in all organs and
tissues of the human body.
NH
N
H
H H
NH2
O
OH
2-amino-3-(1H-imidazol-4-yl)propanoic
acid
Histidine
Histamine
Histidine decarboxylation
-CO2
NH
N
H
H H
H
NH2
2-(1H-imidazol-4-yl)ethan-1-amine

3.  Histamine is stored in the secretory granules of mast cells (pH 5.5) as
positively charged and ionically complexed with negatively charged acidic group
on other secretory granules which constitutes heparin.
 The antigens are proteins or polysaccharides obtained from various source like
dust, pollen, grains, and food stuff etc.
 The principal target cell of immediate hypersensitivity
reactions are mast cells and basophils to generate IgE antibodies
that binds to FC (fragment crystallizable) receptor on the
granules surface.

4. Figure:- A Fc receptor is a protein found on the surface of certain cells – including, among others, B
lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils,
human platelets, and mast cells – that contribute to the protective functions of the immune system

5.  Histamine is an important chemical messenger, communicating information
from one cell to another and is involeved in a variety of complex biological
actions.
 It mainly stored in an inactive bund form, form which its released as a result
of an antigen-antibody reaction, initiated by different stimuli such as venoms,
toxins, proteolytic enzyme, detergents and numerical chemicals.
 Systemically, histamine contracts smooth muscle of the lungs and the GIT and
cause vasodilator low BP and increase heart rate.
 It also causes symptoms such as itching, sneezing, watery eye and running
nose.
 Histamine exerts it’s biological function by interacting with atleast three
distinctly specific receptors H1, H2, and H3.
 The term antihismine has been used to describe a drug that acts on H1 and H2.

6.  Histamine is composed of an imidazole ring, an ethylamine side chain in
which the methylene groups are designed as α and β.
NH N
NH2
1
2
3
4
5
a
b
 The side chain β-CH2 group attached to 4th position of imidazole ring.
 Histamine is an achiral molecule. It exists in trans-gauche rotameric
structures.
Its trans- rotamer possesses affinity for both H1 and H2 receptors whereas its
guache form possesses affinity only for H3 receptor.

8. HISTAMINE RECEPTORS AND THEIR DISTRIBUTION
Histamine shows physiological effects by specific cell surface receptors. These
receptors are of four types i.e. H1, H2, H3 and H4. All these receptors are G-
protein coupled receptors. Histamine receptors, distribution and physiological
function are summarized as follows;
Receptors Distribution Function
H1 Smooth muscle of respiratory and GI
tract uterine tissue, epithelial and
endothelial cells, T-cells, B-cells,
neutrophils, eosinophils and hepatocytes
Pruritis, pain,
vasodilators,
hypertension, headache,
severe allergic response.
H2 Different tissues or gastric cells Gastric acid secretion,
hypotension, headache,
inotropic activity
H3 CNS (cortex, straitum, sub-stantia nigra) Modulate neuro-
transmission
H4 Hematopoietic cells Modulate immune
function

9. STRUCTURE ACTIVITY RELATIONSHIP
H1 RECEPTOR ANTAGONISTS
Based on the pharmacological profile, the H1 antihistamines are divided into
two major groups;
1. First generation or classical antihistamines
2. Second generation or nonsedative antihistamines
The SAR of antihistamines is discussed with reference to the first generation
antihistamines. The structural requirements for H1 antihistamines are shown
below;
X
Ar1
Ar
C
C
N1
2
3
4

10. ARYL GROUPS
 The diaryl substitution is essential for significant H1 receptor affinity. It is
present both in first and second generation antihistamines.
 The optimal antihistamines activity depends on the co- planarity of two aryl
substitutions. These are follows as;
Ar: Phenyl, substituted phenyl and heteroaryl group like 2-pyridyl;
Ar1: aryl or aryl methyl group.
Two aryl rings may be liked e.g. promethzine, cyproheptadine and azatidine.
NATURE OF X
 The X- connecting moiety of H1 antihistamines may be simple carbon chain or
saturated carbon oxygen moiety, which serves as a spacer group for required
pharmacophore.
 The active substitution of X are as follows: X= carbon (mono amino propyl
analogue), oxygen (amino alkyl ether analogue), and nitrogen (ethylene diamine
derivative).

11. ALKYL CHAIN (CH2)n
The carbon chain two or more atoms in H1 antihistamines, which leads to the
distance between the central point of the diaryl ring system and the terminal
nitrogen atom in the extended conformation of these compounds in the range
of 5-6 Aº.
Branching of this carbon chain leads to decrease in antihistamines activity.
If the carbon atom adjacent to the terminal nitrogen atom is branched, the
possibility of asymmetry exists.
C
C
N
R1
R

12. TERMINAL NITROGEN ATOM
The t-N atom should be teriary amine for maximum activity. The t- N may be a
part of heterocyclic ring.
E.g. anatzoline and chlorcyclizine, which are also retains high anithistaminic
activity.
CH N N CH3
Chlorcyclizine

14. Ethylene diamine derivatives N
Ar1
Ar
C C
H
H
H
H
N
CH3
CH3
NAME Ar Ar1
Tripelennamine
Pyrilamine
Methapyrilene
Thonzylamine
Zolamine
N
CH2
N
OCH3H2C
N
S
H2
C
N
N
OCH3H2C
N
S
OCH3H2C

15. Amino alkyl ether analogues
O C C
H
H
H
H
N
CH3
CH3
C
R
Ar2
Ar1
NAME Ar1 Ar2 R
Diphenydramine
-H
Bromodiphenydramine
-H
Doxylamine
-CH3
Carbinoxamine
-H
Medrylamine
-H
Br
N
Cl
N
H3CO

16. example
Cl C
CH3
O CH2 CH2
N
H3C
Clemastine
H
O N CH3
Diphenylpraline

17. Cyclic basic chain analogues
CR1
H
N N R2
NAME R1 R2
Cyclizine -H -CH3
Chlorcyclizine -Cl -CH3
Meclizine -Cl
Buclizine -Cl
C
H2
CH3
C
H
H
C

18. Mono amino propyl analogues
Saturated analogues
CH
Ar1
Ar
CH2 CH2 N
CH3
CH3
NAME Ar Ar1
Pheniramine
Chlorpheniramine
bromopheniramine
N
N
Cl
N
Br

19. Unsaturated analogues
N
Ar
Ar1
NAME Ar Ar1
Pyrrobutamine
Triprolidine
Cl
H2
C
H3C
N

20. Tricyclic ring system
N
S
R
NAME R
Promethazine HCl
Trimeprazine
Methidilazine
CH2 C
CH3
H
CH3
CH3
.HCl
CH2 C
CH3
H
CH2 N
N
CH3

21. Dibenzocyclohepte
nes
N
CH3
Cyproheptadine (periactin)
N
N
CH3
Azatadine
Miscellaneous
N
CH2
CH2
N
H
N
Antazoline
N CH3
Phenindamine

22. Newer agents
S
O
N
H3C
S
O
N
H3C
Cl
Ketotifene 7-chloro Ketotifene
H1 antagonists with nonclassical
structures
H3CO
N
H
N
N
N
CH2
F
Astemizole

23. N
N
N CH3
CH2
O
Cl
Azelastine
Nonsedative H1 antihistamines
Nonsedative antihistamines bind only to peripheral H1receptors and produce
with little or no sedation because of poor CNS penetration and lower affinity
for central histamine activity.
These are divided into two main classes;
 Piperazine derivatives- cetrizine
 Pyridine and piperidine derivatives- Loratadine, Fexofenadine, Terfenadine,
etc.

24. N
N
C2H5OOC
Cl
Loratadine
Cl N N
O
COOH
Cetirizine
Inhibition of histamine release (mast cell stabilizers)
Cromolyn sodium
O
NaOO
C
O CH2O
H
C
OH
O
O
O
COONa

25. Thank You!!!