Anti histaminic agents medicinal chemistry

1. School of Pharmaceuticals and Population Health Informatics,
Faculty of Pharmacy, DIT University,
Dehradun, Uttarakhand-248009, India
SUBJECT CODE - BP501T
COURSE & YEAR - B. Pharm. & 3rd
FACULTY NAME - Dr. Shashank Shekher Mishra
Medicinal Chemistry-II
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2. Anti HistaminicAgents
PART- 1
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3. Autocoids
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 Autos- Self, Akos- healing substance or remedy
 Diverse substance produced by variety of cells in the body
having intense biological activity, but act locally.
 Local hormones
 Classical autocoids-
 Amine autocoids- Histamine, 5-hydroxytryptamine
 Lipid derived autocoids- Prostaglandins, Leukotrienes,
Platelet activating factor
 Peptide autocoids- Plasma kinins, Angiotensin

4. 4
Histamine
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 Tissue amine, Histos- Tissue
 Present within storage granules of mast cell.
 Histamine rich tissues = Skin, Gastric and intestinal
mucosa, Lungs, Liver, Placenta.
 Major mediator of allergy and inflammatory process.
 Significant role in the regulation of gastric acid secretion,
neurotransmission and immune modulation.
 Histamine is also present in blood, most body secretions,
venoms and pathological fluids.

5. 5
Histamine
Synthesis,storageanddegradation
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 β imidazolylethylamine
 Synthesized locally from the
amino acid histidine and
degraded rapidly by
oxidation and methylation.
 Release = Histamine
contain positive charge held
by acidic protein and
heparin (negative charge).
 When granules are broken by exocytosis = Na+ is exchanged by Histamine.
Decarboxylation of the amino acid L-Histidine
yields Histamine

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Pathophysiologicalroles
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 Gastric secretion:
 Allergic phenomena:
Exposure of an antigen to a previously
sensitized(exposed) subject can immediately
trigger allergic reactions
¨If sensitized by IgE antibodies attached to their
surface membranes, mast cells will degranulate
when exposed to the appropriate antigen &
release histamine, ATP and other mediators
 As transmitter: believed to be the afferent transmitter which initiates
the sensation of itch and pain at sensory nerve endings.
 Inflammation: mediator of vasodilatation

7. 7
Histamine receptors

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15. 15
Drugs that block the histamine release

16. 16
Drugs having dual action

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1. Which class of antibody is associated with an
allergic reaction?
a) IgE
b) IgA
c) IgM
d) IgG

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2. Which of the following enzyme is essential for
the conversion of histidine to histamine?
(a)Histidine amylase
(b)Histidine hydrolase
(c)Histidine decarboxylase
(d)Histidine phosphorylase

20. 20
3. Which of the following histamine receptor increases
the release of gastric acid?
(a)H1 receptor
(b)H2 receptor
(c)H3 receptor
(d)H4 receptor

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1. First-Generation Antihistamine Classes
A. AMINOALKYL ETHERS (ETHANOLAMINES)
B. ETHYLENEDIAMINES
C. PIPERAZINES (CYCLIZINES)
D. PROPYLAMINES (MONOAMINOPROPYL OR ALKYLAMINE DERIVATIVES)
E. PHENOTHIAZINES
F. DIBENZOCYCLOHEPTENES AND DIBENZOCYCLOHEPTANES
2. Second-Generation Antihistamine Classes

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A. AMINOALKYL ETHERS (ETHANOLAMINES)
Diphenhydramine Hydrochloride
2-(diphenylmethoxy)-N,N-
dimethylethanamine hydrochloride
(Benadryl)
Dimenhydrinate
The 8-chlorotheophyllinate (theoclate)
salt of diphenhydramine, 8-
chlorotheophylline
2-(diphenylmethoxy)-N,N-
dimethylethylamine (Dramamine)
Recommended for nausea of motion
sickness and for hyperemesis gravidarum
(nausea of pregnancy)
Other therapeutically useful derivatives of
diphenthydramine have been obtained by para
substitution
of methyl (methyldiphenhydramine), methoxy
(medrylamine), chloro (chlorodiphenhydramine), or
bromo
(bromodiphenhydramine) on one of the phenyl rings.
N, N-dimethylethanolamine derivatives

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A. AMINOALKYL ETHERS (ETHANOLAMINES)
Bromodiphenhydramine Hydrochloride
2-[(4-bromophenyl)-phenylmethoxy]-N, N-
dimethylethanamine hydrochloride
(Ambodryl Hydrochloride)
Doxylamine Succinate
The acid succinate salt (bisuccinate) of
doxylamine, 2-[-[2-(dimethylamino)ethoxy]-
-methylbenzyl]pyridine bisuccinate
(Decapryn Succinate)

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A. AMINOALKYL ETHERS (ETHANOLAMINES)
Carbinoxamine Maleate
bimaleate salt, (d, l)-2-[p-chloro--[2-
(dimethylamino)ethoxy]benzyl]pyridinebimalea
te (Clistin)
Clemastine Fumarate
Dextrorotatory clemastine,
R,R-2[2[1-(4-chlorophenyl)-1-
phenylethoxy]ethyl]-1-
methylpyrrolidine hydrogen furnarate

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B. ETHYLENEDIAMINES
Thonzylamine
Methapyrilene
Pyrilamine
Maleate
Tripelennamine
Hydrochloride

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C. PIPERAZINES (CYCLIZINES)
Cyclizine
Hydrochloride
Chlorcyclizine
Hydrochloride Meclizine
Hydrochloride
Buclizine
Hydrochloride

27. 27
D. PROPYLAMINES (MONOAMINOPROPYL OR ALKYLAMINE DERIVATIVES)
Pheniramine Maleate Chlorpheniramine
Maleate
Brompheniramine
Maleate

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Pyrrobutamine
Phosphate
Triprolidine Hydrochloride

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E. PHENOTHIAZINES
Promethazine
Hydrochloride
Trimeprazine Tartrate

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F. DIBENZOCYCLOHEPTENES AND DIBENZOCYCLOHEPTANES
The dibenzocycloheptene and dibenzocycloheptane
antihistamines may be regarded as phenothiazine
analogs in which the sulfur atom has been replaced by an
isosteric vinyl group or a saturated ethyl bridge.
Azatadine Maleate
Cyproheptadine
Hydrochloride

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Miscellaneous
- Diphenylpyraline Hydrochloride
4-(diphenylmethoxy)-1-methylpiperidine
Hydrochloride
- Antazoline Phosphate
N-(4,5-Dihydro-1H-imidazol-2-ylmethyl)-N-
(phenylmethyl)aniline
- Phenindamine Tartrate
2-methyl-9-phenyl-2,3,4,9-tetrahydro-1H-
indeno[2,1-c]pyridine

32. 32
2. Second-Generation Antihistamine Classes
-lower sedation potential and reduced binding affinities for nontarget
proteins
including muscarinic, adrenergic, and serotonergic receptors.
Terfenadine
Astemizole
- Astemizole and terfenadine proved to be “nonsedating” and target-receptor
selective.
- Serious cardiovascular toxicities (QT prolongation and arrhythmias).
Both astemizole
and terfenadine
have been
withdrawn from
the U.S. market.

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Further drug design efforts resulted in the discovery of new second-
generation agents, which retained the nonsedating and receptor-
selectivity properties, but lacked the cardiotoxicity of astemizole and
terfenadine.
Acrivastine, an alkene-acid derivative
of
triprolidine
(E)-3-{6-[(E)-1-(4-methylphenyl)-3-
pyrrolidin-1-yl-
prop-1-enyl]pyridin-2-yl}prop-2-enoic acid

34. 34
Cetirizine and Levocetirizine, oxidation metabolites of hydroxyzine
Hydroxyzine
- Does not penetrate or accumulate
in the CNS.
- R-enantiomer is has a 30-fold
higher affinity than the S-
enantiomer, and dissociates
more slowly from H1-receptors.
- Pharmacologically, it displays
the same receptor and CNS
selectivity profile as the
racemate, cetirizine.

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Fexofenadine Hydrochloride
2-[4-[1-hydroxy-4-[4 [hydroxy(diphenyl)methyl]piperidin-1-
yl]butyl]phenyl]-2-methylpropanoic acid
Fexofenadine is a primary oxidative metabolite of
terfenadine.
No sedative or other CNS effects
Does not cross the BBB

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Loratadine
Loratadine is structurally related to the antihistamines azatadine
and cyproheptadine, and to some tricyclic antidepressants.
It differs from azatadine, in that a neutral carbamate group has
replaced the basic tertiary amino moiety, and a phenyl ring has
been substituted with a chlorine atom.
Ethyl 4-(8-chloro-5,6-dihydro-11H-
benzo[5,6]cyclohepta[1,2-b]pyridin-
11-ylidene)piperidine-1-carboxylate

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INHIBITION OF HISTAMINE RELEASE: MAST CELL STABILIZERS
Stabilize mast cells and inhibit the release of histamine and other
mediators of inflammation.
Cromolyn Sodium
- Nedocromil Sodium
- Lodoxamide Tromethamine

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Structure activity relationship
(general structure of the H1 receptor antagonist)
Where , Ar1 = Phenyl group
Ar2 Phenyl, benzyl, pyridyl or thenyl group
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Substitution on aryl group
Replacement of aliphatic N group
With small basic heterocyclic ring
Increased branching on
Substitution between X and N
Modify the potency, metabolism, ability to
reach the site of action & toxicity in vivo.

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Ar1 and Ar2 substituents
These provide bulk producing antagonistic activity
Generally two aromatic rings - phenyl, benzyl, or an isostere
such as pyridyl;
Pyridyl generally results in more potent compounds than
phenyl
If fused must be non–coplanar as in the three ringed structures
related to TCA’s and phenothiazines
Para substitution with small lipophilic groups increases
potency and decreases metabolism due to decreased ring
hydroxylation.
Ortho or meta substitution reduces antihistaminic activity
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40. 40
This diaryl pattern is present in both first- and second-generation
antihistamines.
X
Atom X can be an oxygen, nitrogen, or carbon, which links the side
chain to an “aromatic tail.” The nature of atom X is the basis for the
structural classification of H1 antagonists. The classical H1 antagonists
are divided into six classes based on what X equals:
X =C–O: (Aminoalkyl Ethers)
1. Ethanolamines
2. Propanolamines (clemastine, diphenylpyraline)
X = C
3. Propylamines (Saturated and Unsaturated)

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X = N:
4. Ethylenediamines
5. Piperazines (Cyclizines) and Tricyclics
6. Miscellaneous: This forms the sixth class of traditional
antihistamines and would include many of the newer
antihistamines since they do not fall into one of the older,
traditional, classes.
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42. 42
Mechanismof Actionof H1 antihistamines

43. Uses
Drugs Uses
Diphenhydramine New widely used for the nausea of motion sickness and for
nausea of pregnancy
Tripelennamine 1. Used for euphoriant
2. Tranquillising effect
Pheniramine Used as antihistamanic
Chlorpheniramine 1. Adjunct therapy in anaphylatic shock
2. Allergic and basomotor stimuli, allergic conjunctivitis
3. Allergic rhinitis, in cough medicines
Dexchlorphenirami
ne
Used to treat allergic condition such as hay fever or
urticaria
Promethazine 1. 1st generation H1 receptor antagonist and anti-emetic
2. Strong anticholinergic and sedative/hypnotic effect
3. Previously used as antipsychotic
Cyproheptadine Both antihistamanic and used in hypersensitivity reactions 43

44. Uses
Drugs Uses
Antazoine 1. It is used to releive nasal congestion and in eye drops
Antazoline+nephazoline Relieve symptoms of
allergic conjunctivitis
Clemastine 1. Allergic rhinitis, urticaria (itchy skin rash),anti-emetic
Pyrilamine Allergic rhinitis, incest bites(topically)
Meclizine Anti-emetic and motion sickness
Cetrizine Allergic rhinitis
Astimazole It gives protection against asthma, hay fever, chronic
utricaria
Dimenhydramine+
chlortheophylline
1. Nausea and motion sickness
2. Antiemetic and sedative in housepets
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45. Diphenhydramine hydrochloride
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46. Triprolidine
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47. Promethazine
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48. Thank You
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