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Antihistaminic and drugs acting on GIT:. Histamine is an important chemical messenger. Distributed within the mast cells and released as a result of antigen-antibody ( IgE ) reaction initiated by different stimuli. - PowerPoint PPT Presentation
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Antihistaminic and drugs acting on GIT:Histamine is an important chemical messenger.
Distributed within the mast cells and released as a result of antigen-antibody (IgE) reaction initiated by different stimuli.
This will lead to mast cell membrane alteration and the release of histamine that will interact with certain receptors called histaminic receptors.
NHN
NH2
HistaminePlays an important role as a stimulant of
gastric secretion from the parietal cells.Has neurotransmission role in the CNS
responsible for:Alertness.Hormone release.Feeding and drinking.Sexual behavior.Analgesia.
Histaminic receptorsOf Four types:H1 to H4.
H1-activation: Smooth muscle contraction in GIT, uterus and bronchi. Relaxation of capillaries….. Increase permeability…
results in edema.H2-activation:
Gastric secretion. Hypotension due to vascular dilatation.
H3-activation: Most important in CNS: regulate histamine in the body, by
inhibiting the further synthesis of histamine. H4-activation:
regulate the levels of white blood cell release from bone marrow.
HistamineIt has two basic centers.
At acidic pH it forms the di-cation compoundAt physiological pH it presents as
monocation.
NHN
NH2pka = 9.5
pka = 5.8
pka = 12-14
Anti-allergic agentsAllergy: is the physiological response to a
foreign chemical or physical condition… cause symptoms such as hay fever, pruritus, dermatitis, rashes, and anaphylactic shock (systemic allergic reaction that may lead to death).
Anti-allergic agents block some of the action of histamine.
Histamine as a lead:SAR for histamine:
The amino group should be positively charged and attached to at least one hydrogen atom.
It should have flexible chain between the amino and the aromatic ring.
The heteroaromatic did not have to be imidazole.
All Histamine analogues did not show promising H1-antagonist activity, they have shown either low agonist or no activity.
H1-antagonists:1. Ethylenediamine derivatives:
Phenbenzamine was used as a model for the synthesis of H1-antagonists using the general structure of
NN N
N
Phenbenzamine
NN R1
R2
Ar2
Ar1
Ethylenediamine derivatives
R1 and R2 should be small (CH3) for maximum H1-antagonist activity.
Ar1 and Ar2 can be benzene ring or any other isosteric rings such as heterocycles.
One of the aromatic should be benzyl for better activity which has P-substitution.
NN R1
R2
Ar2
Ar1
Ethylenediamine derivatives
Isosteric rings to benzene:
All H1-antagonists are dispensed as water soluble salts.
NS
N
S
N
N
BioisosterismBioisosteres are groups with similar physical
and chemical properties which produce almost the same biological and pharmacological response or effect.
The aim of using such groups are:Minimizing the possible side effects.Prolong the duration of action.Produce potent agents.Increase physical and biological stability of
drugs
Ethylenediamine derivativesExamples:
NN
N
O
Pyrilamine (mepyramine)
NN
N
Tripellenamine
Aminoalkyl ether analoguesClosely related to ethylenediamine
derivatives.
Examples:
Ar2 O
Ar1
N
ON
Diphenhydramine
ON
N
Doxylamine
ON
ClCarbinoxamine
Cyclic analogues of ethylenediamine
They have mainly CNS depressant effects.Main uses:
In allergy. As antiemetic agents. In motion sickness.
NN
R1
R
Cyclic analogues of ethylenediamineN
N
Cyclizineantiallergic agents
NN
Cl
MeclizinePotent H1-antagonistused in prevention of motion sicknessfor nausea and vomiting
NN
Cl
Buclizinein motion sickness
NN
Cinnarizinein prevention of motion sickness
• All have hydrophobic group attached to the terminal amino group for better activity compared to ethylenediamine derivatives.• They have a rigidified ethylenediamine structure.• Lower incidence of drowsiness.• They have antimuscarinic activity.
Propylamines (monoaminoproprylamines)
Mainly have a phenyl and 2-pyridyl groups, and a terminal dimethylamino moiety.
The hydrophobic linker should have either sp2 or sp3 carbons.
They are less sedating compared to the ethylenediamine derivatives.
The S enantiomer is the most active form.
Ar2 NR1
R2
Ar1
Propylamines (monoaminoproprylamines)
NN
Pheniramine
NN
Chlorpheniramine20-50% more potent than pheniraminelonger duration of actiont1/2 = 12hrs
Cl
NN
Br
Brompheniraminelonger duration of action (t1/2 = 25hrs)same potency as chlorphinarmine
NN
Triprolidinepyridyl and the pyrrolidinomethyl should be trans to each other for superior activity
H1-antagonists with decreased sedative effectsThe major side effect of H1-antagonists is
sedation due to the interaction with cerebral H1 and H3 -receptors.
Strategies to decrease sedation:Increase selectivity to the peripheral compared
to the central H1-receptors. increase polarity of classic H1-receptors to
decrease the ability to penetrate the BBB.
H1-antagonists with decreased sedative effects
NN
OOH
Cl
NN
OOH
Cl
Hydroxyzinecause sedation as s/e
Cetirizinepresents as zwitter-ionic compoundhas reduced sedative s/e
O
OHN
OH
Trefinadine
N
N
F
NH
N
O
AstimizoleHas no sedative effects due to poor penetration of the BBB.Has long duration of action because its metabolite (desmethyl) is also active.
N
N
Cl
O O
Loratidinehigher affinity for peripheral H1-receptors.has long duration of action due to the lipophilic nature and the stable carbamate group.
• these non-sedating antihistamines have greater receptor specificity, lower penetration of blood-brain barrier, and are less likely to cause drowsiness
H2-antagonists: Anti-ulcer agents
H+
K+
Gastrin
+++
H2M3
HistamineAch
Parietal cell
Stomach lumen
Non-parietal cellsNon-parietal cells
H2-antagonists: Anti-ulcer agentsGastric secretion in stomach is controlled by:
1. Acetylcholine: M3-activation which lead to the production of acid.
2. Gastrin hormone: will be released from the G-cells in the antrum … this will interact with Cck2 receptor in the parietal cells to produce the gastric acid.
3. Histamine: will bind to the H2-receptors… gastric acid production.
4. The proton pump: will pump the formed acid (H+) out of the Parietal cells into the stomach lumen.
H2-antagonists: Anti-ulcer agentsThe First approach in synthesizing H2-
antagonists was the use of Histamine as the lead compound to produce antagonist activity.
Can be done by:Adding extra hydrophobic group to the
structure.Varying the polar amino group.Make extension to the ethyl linker between the
amino and the imidazole ring.
Histamine analogues:N
HNNH2
NN
NR1
R2
HistamineHydrophobic analoguesNone were active
NHN
NH2
Was found to be selective H2-agonist
Histamine analogues:The next approach was to vary the polar groups
in histamine with other polar functional groups.The first derivative was N-guanylhistamine:
Has a weak H2-antagonist (partial agonist).The guanidine moiety has a positive charge at
physiological pH which will be distributed over the three nitrogen atoms.
NHN
HN NH
NH2
N-guanylhistamine as a leadN
HN
HN NH
NH2
NHN
S NH
NH2 NHN
HN NH
S
partial agonistpoor antagonist
1. partial agonist2. poor antagonist3. this means that both terminal amines are essential for activity.
NHN
NH
HN
NH2
antagonist activity increased
NHN
NH
HN
NH2
NHN
NH
S
NH2
1. has Neutral thiourea group2. weak antagonist with no agonist activity.
NHN
NH
NH
S
Burimamide1. 100x more potent than N-guanylhistamine2. specific H2 antagonist.
* The imidazole ring proofed to be important for both agonist and antagonist binding. So the pka of this ring should be closer to the histamine one (5.74).* The pka of imidazole from burimamide is 7.25 which means that around 40% of the imidazole ring is ionized.* The side chain of burimamide should be electron withdrawing to make the pka of The ring close to 5.74.
NHN
S
HN
HN
N CN
Cimetidine
ON S N
HNH
NO2
RanitidineFewer s/e than cimetidine10x more active
N
SN
H2NNH2
S
N
NH2
SO2NH2
Famotidine30x more active than cimetidine