H1 and h2 receptor antagonist

Presented by: Shubham Sharma
Pharmaceutical Chemistry
Roll no. : 20029
Presented to : Dr. Ranju Bansal
Professor ,UIPS, Panjab University

6/3/2021
UIPS, PANJAB UNIVERSITY
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CONTENTS
1. INTRODUCTION , SYNTHESIS AND MOA OF HISTAMINE
2. CLASISIFICATION OF H1 ANTIHISTAMINES
3. SAR OF H1 ANTIHISTAMINES
4. SYNTHESIS
5. INTRODUCTION AND MOA OF H2 ANTIHISATMINES
6. SAR , CLINICAL USES AND SYNTHESIS OF H2 ANTIHISTAMINES
7. INTRODUCTION, MOA , CINICAL USES AND SAR OF PPI’S

Histamine is an organic nitrogenous compound
involved in local immune responses as well as
regulating physiological function in the gut and acting
as a neurotransmitter for the brain, spinal cord and
uterus.
Histamine is involved in the inflammatory response and
has a central role as a mediator of itching. As part of an
immune response to foreign pathogens, histamine is
produced by basophils and by mast cells found in
nearby connective tissues.
HISTAMINE
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SYNTHESIS AND METABOLISM
 Histamine is derived from the decarboxylation of the amino acid
histidine, a reaction catalyzed by the enzyme L-histidine
decarboxylase. It is a hydrophilic vasoactive amine.
 Once formed, histamine is either stored or rapidly inactivated by
its primary degradative enzymes, histamine-N-methyl
transferase or diamine oxidase. In the central nervous system,
histamine released into the synapses is primarily broken down by
histamine-N-methyl transferase, while in other tissues both
enzymes may play a role.

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Continued….

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HISTAMINE RECEPTORS AND ITS MECHANISM OF ACTION

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H1-ANTIHISTAMINES
 H1-antihistamines are not receptor antagonist, but are inverse agonist in that they produce
the opposite effect on the receptor to histamine. Consequently, the preferred term to define
these drugs is “H1 antihistamines” rather than “H1 antagonist”.
Clinical Uses of Antihistamines
 Allergic rhinitis (common cold)
 Urticaria (hives)
 Pruritus (atopic dermatitis, insect bites)
 Anaphylactic reactions (severe allergies)
 Nausea and vomiting (first generation H1- antihistamines)
 As anti-tussives Eg: diphenhydramine.
 As anti-emetic Eg: meclizine.
 In “parkinsonism” Eg: promethazine , diphenhydramine.
 In drug induced “acute dystonias” Eg: diphenhydramine, promethazine.
 To treat “motion & morning sickness” Eg: cyclizine, promethazine.
 To treat “vertigo” conditions Eg: cinnarizine.

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ADVERSE EFFECTS
Associated with the first generation H1-antihistamines and due to their lack of
selectivity for the H1 receptor and anti-cholinergic activity. Side effects are due to CNS
depression:
 Sedation
 Dizziness
 Tinnitus (ringing in the ear)
 Blurred vision
 Euphoria
 Anxiety
 Insomnia
 Dry mouth/dry cough
 Newer second generation H1-antihistamines are more selective for the peripheral
histamine receptors and have far less side effects (drowsiness, fatigue, headache,
nausea and dry mouth) .

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Development of antihistamines began by the discovery of piperoxam.
The drugs shown below will inhibit the action of released histamine:

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Note ; this structure resembles with structure of anticholinergics drugs.

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AMINOALKYL ETHERS (ETHANOLAMINES)
Diphenylpyraline
 Piperidine is introduced

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 Pyrrolidine is introduced

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1. These are characterized by presence of oxygen connecting moiety.
2. Most compounds in this series are simple N,N-dimethyl ethanolamine derivatives.
3. Clemastine differs from basic structural pattern.
4. Most amino alkyl ethers are optically active.
5. Replacement of one of the phenyl rings of the diphenydramine with a 2-pyridyl
group as in doxylamine will enhance antihistaminic activity.
6. This amino alkyl ethers have to penetrate the BBB and occupy central H1 receptor
resulting the drowsiness.
7. Conversion to a quaternary ammonium salt does not alter the antihistaminic
activity but does increases in anticholinergic action.
STRUCTURE ACTIVITY RELATIONSHIP

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ETHYLENE DIAMINE DERIVATIVES
 2-pyridyl group is introduced
 2-thienyl methyl group is introduced
 Pyrimidine is introduced

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1. These are characterized by nitrogen connecting atom.
2. R1 and R2 should be small (CH3) for maximum H1-antagonist activity.
3. Ar1 and Ar2 can be benzene ring or any other isosteric rings such as heterocycles.
4. One of the aromatic should be benzyl for better activity which has P- substitution.
5. Phenbenzamine was first clinically useful member.
6. Replacement of phenyl moiety of Phenbenzamine with a 2-pyridyl system yielded
“tripelennamine”.
7. Replacement of benzyl group of tripelennamine with a 2-thienylmethyl group
provided “methapyriline”.
8. Replacement of tripelennamine with 2-pyridyl group with a pyrimidinyl moiety
yields “thonzylamine”. The anticholinergic & antiemetic action of these
compounds are low.

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PROPYLAMINE DERIVATIVES

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1. Phenyl substituent at P-position replaces with “Cl” is
chlorpheniramine & “Br” is bromopheniramine.
2. These halogenated pheniramines are more potent & have a
longer duration of action.
3. The agents in this class produce less sedation than the other
classical antihistamines.

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CONTINUED…

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PIPERAZINE DERIVATIVES

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Note : Cetrizine belongs to second generation h1 antihistamines

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1. These are ethylene diamine derivatives.
2. Connecting moiety(X) is CHN group.
3. These are moderately potent, with low incidence of
drowsiness, slow onset of action & exhibit peripheral &
central antimuscarnic activity.
4. Primary structural difference is nature of Para aromatic ring
substituent.

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PHENOTHIAZINE DERIVATIVE

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1. Phenothiazine derivatives that contain a 2/3 carbon branched alkyl chain between
alkyl chain between the ring system and terminal nitrogen atom.
2. This differs the phenothiazine’s from antipsychotic series in which an unbranched
propyl chain is required.
3. Promethazine, the parent member of this series is moderately potent & with
prolonged action & pronounced sedative side effects.
4. The combination of lengthening of side chain & substitution of lipophilic groups in
2nd position of aromatic ring results in compounds with decreased antihistaminic
activity & increased psychotherapeutic properties.
METABOLISM: These compounds undergo mono-di & N- dealkylation , sulfur
oxidation, aromatic oxidation at 3rd position to yield phenol & N-oxidation.

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PIPERIDINE DERIVATIVES
NOTE:
• Cyproheptadine and azatidine can also be kept under
heptanes .
• Loratidine belongs to 2 generation h1 antihistamines.

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 These are the phenothiazine analogues in which sulfur atom is replaced by an isosteric
vinyl group (cyproheptadine) or saturated ethyl bridge (AZATIDINE).
Other second generation H1 antihistamines
Note : Cetrizine and Loratidine already has been covered earlier.

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CONTINUED…
 Terfenadine is a long acting h1 antagonist.
 Fexofenadine is a primary oxidative metabolite of terfenadine and do not cross BBB.
 Desloratidine is an active metabolite of loratidine.
Drugs which will inhibit the release of histamine

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 These drugs act by stabilizing the mast cells & inhibit the release of
histamine & other mediators of inflammation.
 Natural product khellin led to the development of bis compounds.
 Cromolyn nasal solution used for the prevention & treatment of
allergic rhinitis.
 Oral concentrate used to treat the histaminic symptoms of
mastocytosis.
CONTINUED…

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PROMETHAZINE SYNTHESIS

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DIPHENYDRAMINE SYNTHESIS

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H2 RECEPTOR AND ITS MECHANISM OF ACTION
H2 receptors are mainly present in the stomach over the parietal cells which is responsible for
binding with the histamine and thus induce acid release while other receptors present over there
will just enhance its action and have a very little role in acid secretion.

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H2 RECEPTOR ANTAGONIST
 H2 antagonist are competitive antagonist of histamine

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H2 ANTAGONIST
IMIDAZOLE RING
THIAZOLE RING

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FURAN RING
THIAZOLE RING

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RANITIDINE SYNTHESIS

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CLINICAL USES:

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PROTON PUMP INHIBITORS
 They are prodrugs that activate in acid environment. After absorption, the active
metabolite diffuses into the parietal cells and accumulates in the acidic secretory
canaliculi.
 The consumption of food stimulates acid secretion and acid secretion activates PPIs.
Then activated PPI is converted to a sulfenamide in the acidic secretory canaliculi
of the parietal cell.
 The sulfenamide interacts covalently with sulfhydryl groups in the proton pump
and make complex, thereby irreversibly inhibiting its activity.
Proton Pump Inhibitor Blocking the H+/K ATPase

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CONSIDER IT AS OMEPRAZOLE

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 Dyspepsia
 Peptic ulcer
 Gastro esophageal reflux disease (GERD)
 Laryngopharyngeal reflux
 Stress gastritis prevention
 Zollinger-Ellison syndrome
Proton Pump Inhibitor Medical Uses

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 The Substituted pyridine ring, substituted benzimidazole moiety & methyl sulfinyl chain
connecting these two is essential for the biological effect.
 Biological activity & chemical stability largely depends on their substitution pattern.
 Pyridine substitution compared to timoprazole 4-methoxy group in the pyridine ring increases
the biological activity by enhancing nucleophilicity of pyridine nitrogen atom.
 A 4-fluro alkoxy substitution combining lipophilicity & electron demanding properties results
strong inhibitory activity. Eg: Lansoprazole SAVIPRAZOLE
 Benzimidazole substitution by electron demanding group leads to strong activity.
 Benzimidazole substitution by electron accepting group leads to less activity.

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1. TIMOPRAZOLE
Discovered in 1975
2. OMEPRAZOLE
 A derivative of timoprazole, omeprazole,
was discovered in 1979, and was the first
of a new class of drug that control acid
secretion in the stomach, a proton pump
inhibitor (PPI).
 Addition of 5-methoxy- substitution to
the benzimidazole moiety of omeprazole
was also made and gave the compound
much more stability at neutral pH.
3. LANSOPRAZOLE
Lansoprazole was the second of the PPI
drugs to reach the market, being launched in
Europe in 1991 and the US in 1995.
It has no substitutions at the benzimidazole
but two substituents on the pyridine:
 Methyl group at position 3.
 Trifluoroethoxy group at position 4.
The drug is a 1:1 racemate of the
enantiomers dexlansoprazole and
levolansoprazole.

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Pantoprazole was the third PPI and was
introduced to the German market in
1994. It has a difluoroalkoxy sidegroup
on the benzimidazole part and two
methoxy groups in position 3 and 4 on
the pyridine. Pantoprazole was first
prepared in April 1985 by a small
group of scale-up chemist.
4. PANTOPRAZOLE 5. RABEPRAZOLE
It is similar to lansoprazole in having no
substituents on its benzimidazole part and a
methyl group at site 3 on the pyridine, the
only difference is the :
Methopropoxy substitution at position 4
intstead of triflouroethoxy group on
lansoprazole

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6. ESMOPRAZOLE
Esomeprazole magnesium
(Nexium) received its first
approval in 2000 and
provided more pronounced
inhibition of acid secretion
and less inter-patient
variation compared to
omeprazole.
7. DEXLANSOPRAZOLE
Dexlansoprazole was launched as a follow
up of lansoprazole in 2009.
dexlansoprazole is an R- enantiomer of
lansoprazole, marketed as Dexilant. After
oral appliance of the racemic lansoprazole,
the circulating drug is 80%
dexlansoprazole. Moreover, both
enantiomers have similar effects on the
proton pump

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REFERENCES
1. JOHN H.BLOCK & JOHN M. WILSON& GISVOLD’S - Organic Medicinal &
Pharmaceutical chemistry. (Pg.): 698 – 728.
2. D.SRIRAM & P.YOGEESWARI -Medicinal chemistry. (Pg.): 278 – 302 .
3. BERTRAM G.KATZUNG, SUSAN B.MARTERS ANTHONY J.TREVOR -
Basic & Clinical pharmacology (Pg.) : 277 .
4. K.D TRIPATHI Essentials of Medical pharmacology. (Pg.): 159 – 160.
5. FOYE’S Principles of Medicinal chemistry. (Pg.): 1045.

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THANK YOU

H1 and h2 receptor antagonist

H1 and h2 receptor antagonist

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