Advanced Medicinal Chemistry: H1&H2 antagonists

1. H1 & H2
ANTAGONISTS
Presented by,
Sapna Sivanthie Suresh Kumar
M.Pharm. (Pharmaceutical Chemistry)
Amritha School of Pharmacy, Kochi

2. H1 ANTAGONISTS

3. INTRODUCTION
 Anti-histamines – drugs that compete with histamines for their receptors
namely H1 and H2 to cause inhibition of histamine action.
 Histamine – β imidazoyl ethylamine derivative
 Histamine is synthesized by decarboxylation of naturally occurring
amino acid histidine.
NH
N
NH2

4. L-histidine decarboxylase
-CO2
Histidine Histamine

5. low blood
pressure
Increases
heart rate
Immediate
allergic and
inflammato
ry response
Gastric acid
release
Central
nervous
system
neurotrans
mitter
contracts
smooth
muscle
vasodilation
Actions of Histamine

6. Histamine Receptors
• Found in smooth
muscle, bronchi, blood
vessels etc.
• Contains 7 –
transmembrane domain
characteristic G-
protein receptor
• Found in tissues of
myocardial cells and
cell membrane of
acid secreting cells.
• characteristic G-
protein receptor
Histamine
receptors
H1 receptors H2 receptors H3 receptors H4 receptors
• Presynaptic receptor
• Influences the release
of histamine and
other
neurotransmitters
from neurons
• Eosinophils,
Neutrophils, CDT4
cells

8. Histamine
Inhibitors
Histamine Release
inhibitors
Released Histamine
Inhibitors
1. H1 antagonist Antihistamines
2. Anti ulcer agents
i. Drugs to neutralize acid
ii. Drugs to decrease HCl secretion
a. H2 receptor antagonist
b. Proton Pump Inhibitors
iii. Mucosal protective agents
iv. Antibiotic regimens

9. Histamine Release Inhibitors
• Mast cell stabilizers
• Agents stabilize mast cell  inhibit the release of histamine & other
mediators of inflammation
• Mainly mediators of inflammation associated with asthma (neutrophils,
eosinophils, mast cells, etc)
Eg :
CHROMOLYN SODIUM
NEDOCROMIL SODIUM
O
O
O
O
O
O
O
O
OH
O
O
OH
O
H
Na
Na
O
N
C
H3
CH3
O
O
O
O
O O
C
H3 CH3
Na Na

10. Released Histamine Inhibitors
1. H1 Antagonist Antihistamines
• Also known as first-generation anti-histamines.
• The 1st generation , H1 antihistamines are useful in the treatment of
allergic responses like hay fever, urticaria, rhinitis and food allergy.
• The side effects of these agents are sedation, drowsiness, blurred
vision, dry mouth, CNS depression etc.
• These are overcome in 2nd generation antihistamines.

11. • Prevent physiological action of histamine rather than opposing
histamine action.
• All H1 antagonists have similar pharmacological action but mainly
differ in their sedative property.
Mechanism of Action

12. Histamine is a tissue amine that is responsible for
symptoms of allergies, such as runny nose or sneezing.
H1 antagonists will prevent the physiological action of
histamine.
So they are used for relieving the symptoms of allergic
reactions such as hay fever, rhinitis, pruritis, common cold,
motion sickness, vertigo etc.

13. Structural Activity Relationship

14. The Ar group may be phenyl, substituted phenyl, or hetero aryl
group such as 2-pyridyl.
Ar’ is a second aryl or aryl methyl group
X is a connecting atom of O, C or N.
(CH2)n is a carbon chain usually ethyl.
N-RR’ represents basic terminal amine function. The diaryl
substitution is essential for significant H1 affinity.

15. The nitrogen should be 3 ֯ amine in nature for maximum
antihistaminic activity. The ‘N’ may also form a part of heterocyclic
moieties like piperidine or piperazine.
The group present between nitrogen atom and group X may be
saturated or unsaturated or substituted.
Many antihistamines contain a carbon atom in the connecting
atom (X) are chiral and exhibit stereo selective receptor binding.
 Eg: S-configuration of Pheniramine series has more affinity
for H1 receptor.

16. CLASSIFICATION OF ANTIHISTAMINES
ANTIHISTAMINES
FIRST GENERATION
ANTIHISTAMINES
SECOND GENERATION
ANTIHISTAMINES
TOPICAL
ANTIHISTAMINES

17. CLASSIFICATION OF ANTIHISTAMINES*
A. First Generation Antihistamines
1. Aminoalkyl ethers: Diphenhydramine, Dimenhydrinate, Doxylamine,
Carbinoxamine
2. Ethylene diamines: Tripelennamine, Pyrilamine.
3. Piperazine derivatives: Cyclizine, Chlorcyclizine, Meclizine
4. Propylamine derivatives: Chlorpheniramine, Pheniramine,
Triprolidine.
5. Phenothiazine derivatives: Promethazine, Trimeparzine, Methdilazine

18. 6. Dibenzocycloheptenes: Cyproheptadiene, Azatadine.
7. Miscellaneous drugs: Ketotifen, Antazoline
Dimethindene Maleate.
B. Second Generation Antihistamines
1. Piperazine derivative:Cetrizine,
2. Pyridine and Piperidine derivative : Fexofenadine, Loratidine, Astemizole
C. Topical Antihistamines
Levocarbastine, Azelastine, Ketotifen, Epinastine.

19. A. First Generation Antihistamines
2 – (Diphenyl methoxy) –N,N’ –dimethyl ethanamine
DIPHENHYDRAMINE *
1. Aminoalkyl ethers:
Ar C O (CH2)n N
R
R
R
R

20. Synthesis*:
DIPHENHYDRAMINE
Uses: It exhibits antiemetic, antitussive, and sedative properties

21. 2. Ethylenediamines
TRIPELENNAMINE

22. Synthesis:
USES: It is used in the treatment of hay fever, urticaria and other mild allergic
conditions

23. 3. Piperazine Derivatives:
CYCLIZINE

24. Synthesis:
USES: It is used to control post-operative and drug induced vomiting and motion sickness.

25. 4. Propylamine derivatives
CHLORPHENIRAMINE
Cl C
H
CH2
C
H2
N CH3
C
H3
N
3-(4-chlorophenyl)-N,N-dimethyl-3-(pyridin-2-yl)propan-1-amine

26. CH3
Cl
MgBr
+
N
CH
O
Cl C
H
N
OH
Cl CH2
N + N
CH3
CH3
CH2
CH2
Cl
NH2
Na
Cl
H
-
(i)Nu-Addition
(ii)Hydrolysis
Catalytic reduction
p-chloro-phenyl
magnesium bromide
Pyridine 2 aldehyde
(4-chlorophenyl)(pyridin-2-yl)methanol
2-[(4-chlorophenyl)methyl]pyridine
Cl C
H
CH2CH2
N
C
H3
CH3
N
N,N –dimethyl amino chloroethane
CHLORPHENIRAMINE
Synthesis:
Synthesis:

27. 4. Phenothiazine derivatives
PROMETHAZINE
USES: It is used in the symptomatic relief of hypersensitive reactions like utricaria,
rhinitis, conjunctivitis and angioedema.urticaria
S
N
CH2
C
H
C
H3
N
C
H3
CH3
N,N-dimethyl-1-(10H-phenothiazin-10-yl)propan-2-amine

28. S
N
CH2
C
H
C
H3
N
C
H3
CH3
C
H3 C
CH3
N
CH3
CH3
Cl
NH2
Na
S
NH
+ + - NH3
10H-phenothiazine sodium azanide 2-chloro-N,N-dimeth
ylpropan
-2-amine
PROMETHAZINE
Synthesis:
USES: Antihistaminic, antiemetic, tranquilizer, potent analgesic and sedative drugs.

29. 5. Dibenzocycloheptenes
CYPROHEPTADIENE
N
CH3
4-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-ylidene)-1-methylpiperidine
USES: Antihistaminic, antiserotonin properties, Antipruritic agent

30. 5. Miscellaneous Drugs
KETOTIFEN
USES: Antiallergic, for prophylactic treatment of asthma
S
NH
O
4-(piperidin-4-ylidene)-4,9-dihydro-10H-benzo[4,5]cyclohepta[1,2-b]thiophen-10-one

31. B. Second Generation Antihistamines
USES: Antihistaminic to treat allergic conditions.
1. Piperazine Derivative
CETRIZINE

32. 2. Pyridine and Piperidine derivative
LORATADINE
USES: Non- sedating antihistamine

33. C. Topical Antihistamines
AZELASTINE
USES:Itching of eyes associated with allergy

35. DOI:https://doi.org/10.1186/1939-4551-1-9-145
H1 antihistamines - Articles
DOI: 10.1111/exd.14602

36. H2 ANTAGONISTS

37. INTRODUCTION
• Antiulcer drugs / anti secretory drugs
• Meant for treatment of peptic ulcer
• Caused due to Helicobacter pylori and even due to excessive/ long -term use
of NSAIDs.
General classification
Anti ulcer agents
i. Drugs to neutralize acid – Antacids – Al(OH)3, Mg(OH)2
ii. Drugs to decrease HCl secretion
(a) H2 receptor antagonist- Ranitidine, Cimetidine, Famotidine
(b) Proton Pump Inhibitors-Omeprazole, Rabeprazole, Lansoprezole,
Pantoprezole
iii. Mucosal protective agents- Misoprostol, Sucralfate
iv. Antibiotic regimens- Amoxycyllin, Clarithromycin

38. • The H2 receptor antagonists (H2RA) are a class of drugs used to block the
action of histamine on parietal cells (specifically the histamine H2 receptors)
in the stomach, decreasing the production of acid by these cells.
• H2 antagonists are used in the treatment of dyspepsia, although they have
been surpassed in popularity by the more effective proton pump inhibitors.
H2 RECEPTOR ANTAGONISTS

39. H2 receptor antagonist
Competitively block H2 receptor
Histamine cannot act
Decrease cAMP formation
Reduce acid secretion
Healing of Ulcer
Mechanism of Action

40. • SAR is derived from the structure of Cimetidine
• Imidazole ring is not required for competitive antagonism of histamine H2
receptor. Other heterocyclic, which enhance the potency and selectivity of H2
receptor antagonism can be used.
• The ring and terminal nitrogen should be separated by four carbon-atom for
optimum activity.
• Isosteric thio ether link is also present in certain drugs.
• The terminal nitrogen-containing functionality should be a polar, non-basic
substituent for maximal antagonist activity.
Structural Activity Relationship

41. CIMETIDINE
N
H
N
C
H3
CH2
S
CH2
CH2
NH
N
H
N
CH3
C
N
N''-cyano-N-methyl-N'-(2-{[(5-methyl-1H-imidazol-4-
yl)methyl]sulfanyl}ethyl)guanidine
Uses:
Treatment of gastric and duodenal ulcer

42. Synthesis:
N
H
N
CH3
C
O
O CH2
CH3
Na/liq.NH3 N
H
N
CH3
CH2
OH
+ CH2 CH2
NH2
S
H
4 methyl-1H-imidazole
5-yl ethyl formate
S CH2
NH2
N
H
N
CH3
CH2
S CH2
NH2
N
H
N
CH3
CH2
C
H3
S
C
S
CH3
N
C
N
dimethyl
cyanocarbonodit
hioimidate
NH
C
S
CH2
NH
S CH2
N
H
N
CH3
CH2
N
C
H3
NH2
-H2O
Cimetidine
2 aminoethane-1 thiol

43. FAMOTIDINE
Uses:
Treatment of gastric and duodenal ulcer, Zollinger- Ellison Syndrome, and heart burn

44. RANITIDINE
Uses:
Treatment of gastric and duodenal ulcer, Zollinger- Ellison Syndrome, and heart burn

45. References :
1. Textbook of Medicinal Chemistry, Second Edition, Volume- I by K.Ilango,
B.Valentina
2. Wilson and Gisvold’s Textbook of Organic Medicinal Chemistry, 11th
edition .
3. Simon FE, Simons KJ. H1 antihistamines: current status and future
directions. World Allergy Organization Journal. 2008;1(9):145-155.
4. Li L, Liu R, Peng C, Chen X, Li J. Pharmacogenomics for the efficacy and
side effects of antihistamines. Experimental Dermatology. 2022
Jul;31(7):993-1004.

46. THANK YOU