ANTIHISTAMINIC AND RELATED

GASTROINTESTINAL THERAPEUTIC
AGENTS
 Outline
• Overview: what is histamine?
• Biosynthesis, Metabolism
• Receptor types and physiological effects
• H1, H2, H3, H4,…
• Chemistry of histamine
• What are antihistamines?
• Classes of histamine antagonists
• H1 receptor antagonists (blockers)
» 1st generation antihistamines
» 2nd generation antihistamines
» 3rd generation antihistamines
• H2 receptor antagonists (blockers)

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What is Histamine? Overview

• a chemical messenger released by cells.

• widely distributed in the body
• acts as a local hormone
• one of the major inflammatory mediator
• the highest concentrations in human tissues:
Lung, stomach and skin [33μg/g tissue]

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Biosynthesis

Synthesized chiefly in
• Mast cells : stomach, liver, L/S intestine, heart and lung
• Basophilic granulocytes: blood

Other sites of synthesis include:

▪ Neurons of the CNS and
▪ Epidermis of the skin

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Termination of Histamine Action
• Cellular uptake
• Metabolism (Major)

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H1 receptors
➢It is found in smooth muscles of intestine,
bronchi, blood vessels, adrenal medulla,
endothelial cell and lymphocytes.
➢Histamine H1 receptors are G-protein linked
receptors. It is sequence of 491 amino acids
residue.
➢H1 - receptors mediate smooth muscle
contraction, increased vascular permeability,
pruritus, prostaglandin, decreased artrio
ventricular conduction time accompanied by
tachycardia and activation of vagal reflexes
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H2-receptors

• They are located on the cell membrane of

acid secreting cells of gastric mucosa and
mediate the gastric acid secretary actions of
histamine.
• The physiological effects of H2-receptor
ligands are mediated by a stimulatory G-
protein coupled receptor.

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H3 and H4 Receptors

H3 Receptor…

Thought to be a GPCR
• May play role in CNS (auto receptors)
• Possible regulation of synthesis and release of Hist.
• Signaling pathway unknown

H4 Receptor…

• GPCR
• Found in intestines, spleen, T-cells and neutrophils
• Suggests role in Immunity.
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 Chemistry and SAR of histamine
• Hydrophilic hetrocyclic molecule
•Contains imidazole ring linked with alkyl amino group
• pka’s 9.40 (aliphatic amine)
5.74 (imidazole N, 2o amine)

There are two tautomeric forms of histamine.

• 4-(β-aminoethyl) imidazole (Nτ-tautomer) and
• 5-(β-aminoethyl) imidazole (N-tautomer)
➢Both forms are active physiologically.
 
5
4 NH2 4 5 NH2
 
1 HN N 3 3 N NH 1
   
2 2

Nτ-tautomer N-tautomer 9
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 What are an antihistamines?

• “Compete against the receptors’ natural substrates’’

• drugs that reduce or eliminate the effects mediated by the
chemical histamine
• The term antihistamine only refers to H1 receptor
antagonists (actually inverse agonists)
• Antihistamines compete with histamine for binding sites at
the receptors. And cannot remove the histamine if it is
already bound

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• Classes of Histamine antagonists
• H1 receptor antagonists (blockers)
» 1st generation antihistamines
» 2nd generation antihistamines
» 3rd generation antihistamines
• H2 receptor antagonists (blockers)

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 1st generation antihistamines
SAR
• 2 aromatic rings, connected to
a central carbon, nitrogen, or
oxygen
• Spacer between central atom
and the amine, usually 2-3
carbons in length. (Can be
linear, ring, branched,
saturated or unsaturated)
• The amine is substituted with d ~ 4-6Ao
small alkyl groups
Ar R
• Chirality at X and having the
rings in different planes X C N
influences potency of the drug H2 n
Ar' R'

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General H1 Receptor Antagonist
Classes of First generation H1 receptor
antagonists
Ar R X n Class of Antihistamines

X C N
H2 n
O 2 Ethanolamines
Ar' R'

Spacer
N 2 Ethylenediamines
General H1 Receptor Antagonist
C 2 Propylamines

• Ethylenediamines
• Ethanolamines
• Alkylamines (Propylamines)
• Tricyclics
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 Ethylenediamines
• These were the first group of clinically effective H1-
antihistamines.They also display a relatively high
frequency of central nervous system depressant
(sedation) and gastrointestinal side effects. The
anticholinergic and antiemetic actions of these
compounds is relatively low compared to most other
classical antihistamines.

Mepyramine (Pyrilamine) Tripelenamine

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 Piperazines/Cyclizines
• The piperazines or cyclizines can also be considered to be
ethylenediamine derivatives or cyclic ethylenediamines
(cyclizines).
• The piperazines are moderately potent antihistaminics with a
lower incidence of drowsiness. They are more useful as
antiemetics and antinauseants and in the treatment of motion
sickness
• Cyclizine HCl is used primarily in the prophylaxis and treatment
of motion sickness. The lactate salt (Cyclizine Lactate Injection
is used for intramuscular injection because of the limited water
solubility of the hydrochloride.
• Chlorcyclizine HCl has an additional ring Cl substituent which
reduces activity. Chlorcyclizine is indicated in the symptomatic
relief of urticaria, hay fever, and certain other allergic conditions

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• Meclizine HCl and Buclizine HCl are N-benzyl substituted piperazines.
• Although it is a moderately potent antihistaminic, meclizine is used
primarily as an antinauseant in the prevention and treatment of motion
sickness and in the treatment of nausea and vomiting associated with
vertigo and radiation sickness.
• Buclizine HCl is highly lipid-soluble and has central nervous system
depressant, antiemetic, and antihistaminic properties

Meclizine
Chlorcyclizine

Cyclizine
17
Buclizine
 Ethanolamines

Diphenhydramine (Nytol/Benedryl)
• Oldest and most effective antihistamine on the
market
•In addition to antihistaminic action,
diphenhydramine exhibits anticholinergic,
antidyskinetic, antiemetic, antitussive, and
sedative properties.
•has antinauseating effect
• also used in motion sickness
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• Drowsiness is a side effect common to the tertiary aminoalkyl ethers,

presumably as a result of the ability of these compounds to penetrate
and BBB and occupy central H1-receptors
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 Dimenhydrinate
Clemastine (Tavist) (Dramamine)
The 8-chloro-theophylline salt of
N diphenydramine

O
O
NH
N
O N
Cl

N N O
Cl

Cl

• Exhibits fewer side effects than

most antihistamines
• Anti-emetic (anti nausea)
• Widely used as an antiprurtic
• Also causes strong sedation
(stops itching)
• Readily crosses the BBB 19
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 • Diphenylpyraline is structurally
related to diphenhydramine with
the aminoalkyl side chain
incorporated in a piperidine ring.
It is a potent antihistaminic.
• Clemastine is structurally related
Diphenylpyraline to chlorodiphenhydramine with
the aminoalkyl side chain
incorporated in a pyrrolidine ring,
and it has an additional benzylic
methyl group

Clemastine

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 Alkylamines (Propylamines)
Long acting
4x active than ethanolamines

• The halogenated pheniramines are significantly more

potent (20-50 times) and have a longer duration of action
than the parent pheniramine.
• These drugs have fewer GI adverse effects, but a greater
incidence of CNS sedation.

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 Akylamines
Brompheniramine
Chlorpheniramine
(Dimetap)
Br

* N
*

• Originally used to prevent N

allergic conditions
• Shown to have antidepressant • Available over the counter
properties and inhibit the
reuptake of serotonin • Used to treat the common cold
by relieving runny nose, itchy,
• The first SSRI was made as a watery eyes and sneezing
derivative of chlorpheniramine

Two optical isomers and d form is active

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Triprolidine

• Used to alleviate the symptoms associated with allergies

• Can be combined with other cold medicine to relieve “flu-like”

symptoms

There are Two geometrical isomers of Triprolidine,

trans form is active 23
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 Tricyclics
• These drugs are structurally related to tricyclic
antidepressants, which explains why they have
cholinergic side effects
• The general structural feature

(Y)n

A B C

R
CH3 CH3
R= -CH3-CH N
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CH3

Y could be CH2, hetro atom, or CH2-hetro atom

When
X = O; Alkyl amino ether
= N; ethylenediamine
= C; propyleneamine 24
Promethazine (Phenergan)

•This drug has extremely strong

S
anticholinergic and sedative effects
• It was originally used as an
N antipsychotic, however now it is most
CH3
commonly used as a sedative or
antinausea drug (also severe motion
N
sickness) and requires a prescription.
• In addition to its antihistaminic action, it
is a potent antiemetic, anticholingeric and
sedating agent, and significantly
potentiates the action of analgesic and
sedative drugs

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 Cyproheptadine
•This drug both an antihistamine and
an antiserotonergic agent
•It is a 5-HT2 receptor antagonist and
also blocks calcium channels
•Used to treat hay fever and also to
stimulate appetite in people with
anorexia
•It is also rarely used to treat SSRI
induced sexual dysfunction and also
Cushing’s Syndrome (high level of
cortisol in the blood) and migraine
headaches
Ketotifen
O
N
• This drug is available in two forms:
an ophthalmic form used to treat
allergic conjunctivitis or itchy red
eyes and an oral form used to
prevent asthma attacks
• It has several adverse side effects
including drowsiness, weight gain,
dry mouth, irritability and increased
nosebleeds
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 Second generation H1-receptor
antagonists
• These are the newer drugs and they are much more
selective for the peripheral H1-receptors involved in
allergies as opposed to the H1-receptors in the CNS
• Therefore, these drugs provide the same relief with many
fewer adverse side effects and non sedating.
• The structure of these drugs varies and there are no
common structural features associated with them
• They are bulkier and but less lipophilic than the first
generation drugs, therefore they do not cross the BBB as
readily.
• Recent studies have also showed that these drugs also
have anti-inflammatory activity and therefore, would be
helpful in the management of inflammation in allergic 27
airways disease. MedChem, Alemu T.
 Second generation H1-receptor antagonists

Acrivastine (Semprex-D) Cetirizine (Zyrtec)

O

Cl O
N OH

• Structurally related to the

ethylenediamines and the
•This drug relieves itchy ethanolamines and thus produce
rashes and hives significant anticholinergic effects.
• Perennial and seasonal allergic and
•It is non-sedating because it vasomotor rhinitis; relief of symptoms
does not cross the BBB from colds, urticaria, angioedema,
readily anaphylactic reactions, pruritus, allergic
conjunctivitis
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Loratadine (Claritin) Terfenadine
O
O CH3

HO
N
OH

Cl
• It was formerly used to treat
allergic conditions
• It is the only drug of its class
available over the counter • In the 1990’s it was removed from
the market due to the increased
• It has long lasting effects and does risk of cardiac arrhythmias
not cause drowsiness because it
does not cross the BBB readily MedChem, Alemu T. 29
Azelastine Levocabastine Olopatadine
(Astelin or Optivar) (Livostin) (Patanol)
N
O

Cl

• It is a mast cell stablilizer

• Available as a nasal spray
(Astelin) or eye drops for • Both of these drugs are used as eye
pink eye (Optivar) drops to treat allergic conjunctivitis
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 Third Generation H1-Receptor Antagonists
• These drugs are derived from second generation
antihistamines
• They are either the active enantiomer or metabolite of
the second generation drugs designed to have
increased efficacy and fewer side effects

Levocetrizine (Zyzal)
• This drug is the active enantiomer of cetirizine and is
believed to be more effective and have fewer adverse
side effects.
• Also it is not metabolized and is likely to be safer than
other drugs due to a lack of possible drug interactions
• It does not cross the BBB and does not cause
significant drowsiness
• It has been shown to reduce asthma attacks by 70% in
children
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 Deslortadine (Clarinex)
Fexofenadine (Allegra)

• It was developed as an
• It is the active metabolite of
alternative to Terfenadine
Lortadine
• Fexofenadine was proven to be
• Even though it is thought to be
more effective and safe
more effective, there is no
concrete evidence to prove this

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 Clinical Uses of Antihistamines/H1
Antagonists
• Allergic rhinitis (common cold)
• Allergic conjunctivitis (pink eye)
• Allergic dermatological conditions
• Urticaria (hives)
• Angioedema (swelling of the skin)
• Pruritus (atopic dermatitis, insect bites)
• Anaphylactic reactions (severe allergies)
• Nausea and vomiting
• Antiasmathic
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H2 Histamine antagonists.
In the beginning—ulcer therapy in 1964
DISORDERS associated with elevated
secretion of gastric acid
NSAID-Associated Ulcer
Zollinger-Ellison Syndrome
Helicobacter Pylori (H. Pylor~)
Reflux Esophagitis/GERD

▪Ulcers are localized erosions of the mucous membranes of

the stomach or duodenum. It is not known how these ulcers
arise, but the presence of gastric acid aggravates the
problem and delays recovery.

▪In the early 1960s, the conventional treatment was to try and
neutralize gastric acid in the stomach by administering bases
such as sodium bicarbonate or calcium carbonate.
▪However, the dose levels required for neutralization were large
and caused unpleasant side-effects and it is not effective

A better approach would be to inhibit the

release of gastric acid at source.

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 Acetylcholine
Oesophagus

Histamine Gastrin
+
+ M3
+
H2 Cck2

cAMP
+
+ +
Parietal
Cells

-
Stomach H+ Cl

Stomach
HCl

Antrum
Pyloric Receptors
Sphincter
Ion channel
Duodenum
Proton pump

Anticholinergic drugs ╠► unwanted side effects

Gastrin receptor blocker ╠► unsuccessful MedChem, Alemu T.
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 H2 Histamine antagonists.
Gastric receptors are pharmacologically distinct.
The classic H1 antagonists don’t interact with H2 receptors.
No effect on gastric acid release

Developing a Lead Compound

• A classic example of rational drug design
• work began in 1964
• There was no lead compound to work from
• Take a closer look at Histamine

36
 Burimamide
• Burimamide is the prototype H2-receptor antagonist.
• highly specific competitive antagonist of histamine at H2
receptors,
• 100 times more potent than Nα-guanylhistamine.
• It is the 4 carbons bridged analogue with guanidine moiety
of Nα-guanylhistamine is replaced with thiourea group as
well as addition of an N-methyl group [provides a
beneficial increase in hydrophobicity ]
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HN Chain extention S
HN NH

N N NH2 N N NHMe
H H

Guanylhistamine Burimamide
37
Metiamide
• analogue of burimamide with side-chain electron
withdrawing atom (sulfur) inserted into the side-chain
• an electron donating methyl group added at position 4 of
the imidazole ring

CH3
HN S
S
N N NHMe
H

• increase the population of N-H tautomer which affords

enhanced H2 receptor affinity.
• Maintain the preferred conformation of metiamide
– methyl group acts as a conformational blocker
• Metiamide is ten times more active than burimamide

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 Cimetidine
Cimetidine inhibits H2 receptors and thus inhibits gastric acid release.
The drug does not show the toxic side-effects observed for metiamide and
has been shown to be slightly more active.
• The cyanoguanidine moiety acts as a bio-isostere for the thiourea group.
• Both groups are planar and of similar geometry.
CH3 CN
• Both groups are polar but essentially neutral. HN N
• Both groups have high dipole moments. S
N NHMe
• Both groups have low partition coefficients. N H

• They are weakly basic and also weakly acidic such that they are un-ionized at
pH 7.4 and hence possess enhanced antagonistic activity

S NH
H
N NHMe
N NHMe N NHMe
H H
Guanidine N
Thiourea
Drop in activity but no agonist CN
Toxic side effects
activity! Cyanoguanidine
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 Analogues of Cimetidine

terminal
nitroketeneaminal
+
different
heterocyclic ring
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30 times more
active than
equipotent with ranitidine cimetidine

Structure of some H2 receptor blockers 40

Inhibition of Histamine release (Mast cell
stabilizers)

NaO2C O O CO2Na

O O CH2CHCH2 O O

OH

Cromolyn sodium

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