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)

N

N

Pheniramine

N

N

Chlorpheniramine20-50% more potent than pheniraminelonger duration of actiont1/2 = 12hrs

Cl

N

N

Br

Brompheniraminelonger duration of action (t1/2 = 25hrs)same potency as chlorphinarmine

N

N

Triprolidinepyridyl and the pyrrolidinomethyl should be trans to each other for superior activity

H1-antagonists with decreased sedative effects

The 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

OH

N

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

HN

NH2

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

NCN

Cimetidine

O

N S NH

NH

NO2

RanitidineFewer s/e than cimetidine10x more active

N

SN

H2N

NH2

S

N

NH2

SO2NH2

Famotidine30x more active than cimetidine