Anti histamins are drugs used to prevent the inflamation of histamin

1. Histamine, histamine antagonists
and related Gastrointestinal
therapeutic agents
By :Abebe T.

2. 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)
• Proton Pump Antagonists
• Miscellaneous Gastrointestinal agents

3. 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]

4. 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
When synthesized?

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

6. Receptors
• GPCR, membrane receptors
H1 Receptor
• Human H1 receptor gene encodes for 487 a. as protein.
•shows 40% homology with M1 and M2 receptors
Asp, Asn, and Lys responsible for ligand binding
Asp suggested for recognition site for protonated aliphatic
amine.

7. d
d ~ 4-6Ao
Bulky region
Anionic site
The binding requirements for histamine to the HI

8. H1 receptors
• found in periphery smooth muscle (bronchi, L/S intestine,
B.V), skin and CNS
• Activates PLC
• mediates the increase in vascular permeability induced
by Histamine
• Mediates of Inflammation and allergic response
• V.D BP Shock
» Increased blood flow, redness, itchy eyes, hives
• B.C.
• Sm. Ms. Contraction
– Nausea
• Implicated in neurotransmission, arousal and sexual
behavior.
– sleep disorders

9. H2 Receptor
The human gene for H2 receptor encodes for 359 a. as protein.
† Receptor is smaller
• Asp (recognition site for protonated 1o amine), Thr, and
Asp responsible for binding of imidazole portion
increases cAMP production
• found in the stomach and heart
• mediates the release of gastric acid
» Stomach ulcers
Protonation on the τ-nitrogen is
most important for histamine
binding at H2 receptors.
H
+

10. 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.

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

12. • In aqu. soln, the tautomeric composition of
imidazole ring apparently favors the Nτ-H tautomer
by about 4:1.
• The free base also favors the Nτ-H tautomer.
• Tautomeric composition of imidazole is important
for agonist-receptor interaction.
• Changes of tautomeric composition of analogues
occur with changes in the 4-substituent
• eg. Me Vs Cl
• Proportion of Nτ-H is ↓ed in Cl substituted congener
to 12 %.
• proportion Nτ-H is ↓ed to 70% in Me Substituted
congener.

13. • The binding requirements
– for histamine to the HI and H2 receptors are slightly different.
At the HI receptor, the essential requirements are as follows:
• The side-chain has to have positively charged nitrogen atom with
at least one attached proton. Quaternary ammonium salts lacked
such a proton are extremely weak in activity.
• There has to be a flexible chain between the above cation and a
hetero aromatic ring.
• The hetero aromatic ring has to contain a nitrogen atom with a
lone pair of electrons, ortho to the side-chain.

15. At the H2 receptor,
• The essential structure-activity requirements are the
same as for the HI receptor except that the hetero
aromatic ring had to contain an amidine unit (HN-CH-
N:).

17. ACTIVITY DETERMINED INVITRO on: Guinea pig ileum (H1),Guinea pig atrium (H2)
Guniea Pig cerebral cortex (H3)
N
HN
NH2
Cl
N
HN
NH2
H3C
N
HN
NH2
H3C
N
N
HN
NH2
N
S
NH2
S
HN
NH2
N NH2
N
NH2
Relative H1 activity
Vs histamine
Relative H2 activity
Vs histamine
Relative H3 activity
Vs histamine
Histamine 100 100 100
1.7 12 ND
0.23 39 < 0.008
0.49
1.0 1550
12.7 13.7 ND
26
0.3 < 0.008
0.01 0.1 ND
5.6
2.5
< 0.06
INACTIVE INACTIVE ND

18. • structural studies show that some of its conformations are less
stable than others. In particular, conformation I in Fig. above is
disallowed due to a large steric interaction between the 4-methyl
group and the side-chain.
• The selectivity observed suggests that 4-methylhistamine (and by
inference histamine) has to adopt two different conformations in order
to fit the HI or the H2 receptor.
• Since 4-methylhistamine is more active at the H2 receptor, it implies
that the conformation required for the H2 receptor is a stable one for
4-methylhistamine (conformation II), whereas the conformation
required for the HI receptor is an unstable one (conformation I).

19. SAR (CONTD)
•Addition of other alkyl substituents onto histamine
molecule generally ↓ed potency at H1 and H2 receptors
•Imidazole N-substitution (N1 and N3) with methyl groups
result in inactive agents.
•

20. What are an antihistamines?
• “compete against the receptors’ natural substrate,
histamine, in binding to the receptors “
• 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

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

22. Common Structural Features of
antihistamines
• 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
small alkyl groups
• Chirality at X and having the
rings in different planes
influences potency of the drug
C
H2
N
X
Ar
Ar' R'
R
n
General H1 Receptor Antagonist
d ~ 4-6Ao

23. Classes of First generation H1 receptor
antagonists
• Ethylenediamines
• Ethanolamines
• Alkylamines (Propylamines)
• Tricyclics
C
H2
N
X
Ar
Ar' R'
R
n
General H1 Receptor Antagonist
Spacer
X n
Class of Antihistamines
O 2
Ethanolamines
N 2
Ethylenediamines
C 2
Propylamines

24. Ethylenediamines
• These were the first group of clinically
effective H1-antihistamines
Mepyramine (Pyrilamine)

25. Ethanolamines
• This class has significant anticholinergic side effects and sedation,
however reduced the gastroinestinal side effects
Diphenhydramine (Benedryl)
• Oldest and most effective antihistamine on the
market
• Available over the counter
• Because it induces sedation, it’s used in
nonprescription sleep aids
• Also inhibits the reuptake of serotonin, which
led to the search for viable antidepressants with
similar structures (prozac)
• Removes secretion from respiratory tract
• has antinauseating effect
• also used in motion sickness

26. The 8-chloro-theophylline salt of
diphenydramine
Clemastine (Tavist)
Dimenhydrinate
(Dramamine)
•Exhibits fewer side effects
than most antihistamines
•Widely used as an
antiprurtic (stops itching)
•Anti-emetic (anti nausea)
•Also causes strong sedation
•Readily crosses the BBB

27. Alkylamines (Propylamines)
Long acting
4x active than ethanolamines
• Isomerism is an important factor in this class of drugs, which
is due to the positioning and fit of the molecules in the H1-
receptor binding site
• These drugs have fewer GI adverse effects, but a greater
incidence of CNS sedation.

28. Akylamines
Chlorpheniramine
Brompheniramine
(Dimetap)
•Originally used to prevent
allergic conditions
•Shown to have antidepressant
properties and inhibit the
reuptake of serotonin
•The first SSRI was made as a
derivative of chlorpheniramine
•Available over the counter
•Used to treat the common cold
by relieving runny nose, itchy,
watery eyes and sneezing
*
*
Two optical isomers and d form is active

29. Akylamines
Triprolidine hydrochloride
• 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
trans form is active

30. X
(Y)n
R
A B C
X = O; Alkyl amino ether
= N; ethylenediamine
= C; propyleneamine
Y could be CH2, hetro atom, or CH2-hetro atom
When
Tricyclics
• These drugs are structurally related to tricyclic
antidepressants, which explains why they have
cholinergic side effects
• The general structural feature
R = -CH3-CH
CH3
N
CH3
CH3

31. Promethazine (Phenergan)
•This drug has extremely strong anticholinergic and
sedative effects
• It was originally used as an antipsychotic, however
now it is most commonly used as a sedative or
antinausea drug (also severe morning sickness) and
requires a prescription

32. Cyproheptadine Ketotifen (Zaditor)
•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
• 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

33. Clinical Uses of Antihistamines
• 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 (first generation H1-
antihistamines)

34. side effects
• first generation H1-antihistamines
– 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
• Un coordination, Tremor
• 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)

35. 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.
• 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 airways disease.

36. Second generation H1-receptor antagonists
Acrivastine (Semprex-D)
Astemizole (Hismantol)
•This drug has a long
duration of action
•It suppresses the
formation of edema and
pruritis
•It doesn’t cross the BBB
•It has been taken off the
market in most countries
because of adverse
interactions with
erythromycin and grapefruit
juice
•This drug relieves itchy
rashes and hives
•It is non-sedating because it
does not cross the BBB
readily

37. Cetirizine (Zyrtec)
• Structurally related to the ethylenediamines and the ethanolamines and
thus produce significant anti-cholinergic effects
• Used most often to treat motion sickness, vertigo, nausea, vomiting and
itching (skin rash)

38. Second Generation H1-receptor antagonists
Loratadine (Claritin) Terfenadine
•It is the only drug of its class
available over the counter
•It has long lasting effects and does
not cause drowsiness because it
does not cross the BBB readily
•It was formerly used to treat
allergic conditions
•In the 1990’s it was removed from
the market due to the increased
risk of cardiac arrhythmias

39. Second generation H1-receptor antagonists
Azelastine
(Astelin or Optivar)
Levocabastine
(Livostin)
•It is a mast cell stablilizer
•Available as a nasal spray
(Astelin) or eye drops for pink
eye (Optivar)
•Both of these drugs are used as eye
drops to treat allergic conjunctivitis
Olopatadine
(Patanol)

40. 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

41. Third generation H1-receptor antagonists
Deslortadine (Clarinex) Fexofenadine
(Allegra)
•It is the active metabolite of
Lortadine
•Even though it is thought to be
more effective, there is no
concrete evidence to prove this
•It was developed as an
alternative to Terfenadine
•Fexofenadine was proven to be
more effective and safe

42. H2 Histamine antagonists.
In the beginning—ulcer therapy in 1964
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.
not effective
A better approachwould be to inhibit the release of gastric acidat source.
DISORDERS associated with
elevated secretion of gastric acid
NSAID-Associatkd Ulcer.
Zollinger-Ellison Syndrome
Helicobacter Pylori (H. Pylor~)
Reflux Esophagitis

43. Antrum
Stomach
Pyloric
Sphincter
Oesophagus
Duodenum
Histamine
Acetylcholine
Gastrin
Cck2
M3
H2
Parietal
Cells
Stomach
Proton pump
Receptors
Ion channel
cAMP
+
+
+
+
+
+
+ -
H
HCl
Cl
Anticholinergic drugs ╠► unwanted side effects
Gastrin receptor blocker ╠► unsuccessful

44. 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
to vary the structure of histamine in such a way
that it will be recognized by the receptor but…
H2 Histamine antagonists.

45. The First Hit
• Targeted Functional changes of the
amino group
Partial Agonist
Very weakly antagonist
Nα-Guanylhistamine
H
N
HN
N
NH2
H2N

46. • Compare the structures of guanylhistamine and histamine.
• Both structures contain an imidazole ring and a positively charged group
linked by a two carbon bridge.
• The guanidine group is basic and protonated at pH7.4 so that the
analogue has a positive charge similar to histamine.
However, the charge on the guanidine group
• can be spread around a planar arrangement of the three nitrogens and
• can potentially be further away from the imidazole ring
H
N
HN
N
NH2
H2N
H
N
HN
N
NH2
H2N
H
N
HN
N
NH2
H2N
H
N
HN
N
NH2
H2N
Two alternative binding
sites might be available
for the cationic group

47. This leads to the possibility that the analogue could be interacting with
another binding group on the receptor which is 'out of reach' of histamine.
If most of the analogue molecules bind to the agonist site and the remainder
bind to the antagonist site, then this could explain the partial agonist
activity.
Two alternative binding
sites might be available
for the cationic group
Antagonist
binding
region
Agonist
binding
region
Imidazole
ring
binding
region
Antagonist
binding
region
NH3
HN
N
HN
N
NH3
No interaction as an antagonist Strong interaction as an agonist
Binding as an antagonist
Receptor not activated
Binding as an agonist
Receptor activated
Agonist
binding region
Imidazole ring
binding region
Antagonist
binding region
HN
N
NH
NH2
H2N
HN
N NH
H2N
NH2

48. 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 ]
•
HN
N N
H
NHMe
S
Chain extension
e-withdrawing
H
N NH2
S
Thiourea
H
N NH2
NH2
Guanidine
Neutral Basic
Burimamide
The positive
charge
now restricted

49. • Generally, the H2 antagonistic activity of burimamide is
too low for oral use
– basicity of the imidazole ring
• The imidazole ring of histamine is not ionised when it interacts with
the imidazole binding region
– the agonist Vs antagonist binding mode
CH2CH2NH3
HN
N
H
HN
N
CH2CH2CH2CH2NHCSNHMe
HN
N
Imidazole
pKa = 6.80
Histamine
pKa = 5.74
Ionisation = 3%
Burimamide
pKa = 7.25
Ionisation = 40%
e-withdrawing
e-donating

50. 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
• 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
HN
N
S
N
H
NHMe
S
Me
Electron donating

51. Conformational patterns of 4-methyl histamine

52. kidney damage
and granulocytopenia
Not common
in body
biochemistry
Note guanidine is one of the strongest bases in organic chemistry.
argenine
b/c…….
Metiamide is ten times more active than burimamide
HN
N
S
H
N
Me
NHMe
N
CN
Electron withdrawing
cyanide group

53. N
H
NHMe
S
Thiourea
Toxic side effects
N
H
NHMe
NH
Guanidine
Drop in activity but no
agonist activity!
H
N NHMe
N
CN
Cyanoguanidine
group
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.
• Both groups are polar but essentially neutral.
• Both groups have high dipole moments.
• Both groups have low partition coefficients.
• They are weakly basic and also weakly acidic such that
• They are un-ionized at pH 7.4 and hence possess enhanced antagonistic
activity

54. • Cimetidine first marketed in the UK in
1976

55. Metabolism of cimetidine
.
Cimetidine is metabolically stable and is excreted largely unchanged.
The only metabolites which have been identified are due to oxidation of the
sulfur link or oxidation of the ring methyl group.
cimetidine inhibits the P-450 cytochrome oxidase system in the liver. This
is an important enzyme system in the metabolism of drugs and care must
be taken if other drugs are being taken at the same time as cimetidine,
since cimetidine may inhibit the metabolism of these drugs, leading to
higher blood levels and toxic side-effects.

56. Structure of some H2 receptor blockers
Analogues of Cimetidine
terminal
nitroketeneaminal
+
different
heterocyclic ring
30 times more
active than
cimetidine
equipotent with ranitidine

57. Other Therapies: Proton-Pump Inhibitors…
Proton-
Pump
Inhibitors…
Antrum
Stomach
Pyloric
Sphincter
Oesophagus
Duodenum
Histamine
Acetylcholine
Gastrin
Cck2
M3
H2
Parietal
Cells
Stomach
Proton pump
Receptors
Ion channel
cAMP
+
+
+
+
+
+
+ -
H
HCl
Cl

58. PPIs work by forming a covalent disulfide bond with the ATPase
enzyme, leading to an irreversible inhibition of the pump.
The PPI pharmacophore is
2-pyridylmethylsulfinylbenzimidazole

59. • Benzimidazole are Pro-Drugs
• Form active electrophile in Perietal Cells
• Cys from pump act as Nuclephile.

62. Proton pump inhibitors (PPIs)
• There are 5 PPIs currently on market which includes omeprazole,
esmoprazole, lansoprazole, pantoprazole and rabeprazole
• All the PPIs have pyridyl methylsulfinyl benzamidazole skeleton and
act as pro-drugs, as they are activated when they reach the acidic
canaliculi of parietal cells.

63. •
THE END OF THE
CLASS
10 Q ALL!