Transcript antihistaminic

‫بسم هللا الرحمن‬
‫الرحيم‬
Antihistaminic
drugs
Histamine
NH2
NH2
Ntautomer
Ntautomer
HN
N
N

NH

Tautomers of Histamine
Histamine
is
an
autacoid
i.e
physiologically
active,
endogenous substance that is produced within the body by
decarboxylation of the amino acid Histidine and then stored in
mast cells and basophils. It is released in response to a wide
variety of stimuli
mediating a hypersensitivity
reaction.
Histamine action is terminated by cellular reuptake and
enzymatic inactivation.
Biosynthesis of histamine
NH2
NH2
COOH
HN
N
N
Histidine
NH
Histamine
Nomenclature

5
4
1
HN
N3
2
NH2
NH2



4
5
3
N
NH 1
2
4(5)(2-aminoethyl)1H imidazole
Histamine Receptors
or physiological effects of
histamine
1. H1–receptors : Has a role in hypersensitivity reactions
[Pruritis
,
Increased
vascular
permeability
(oedema,
swelling), Increased prostaglandin generation] and also
Mediate smooth muscle contraction.
2. H2–receptors : mediate the gastric acid secretion as they
are located on the cell membrane of acid secretory cells
of the gastric mucosa
3. H3 – receptor : described in 1999 , modulate histamine
synthesis and release in the CNS.
N.B. H4 subtype is recently discovered in 2000 and was
suggested to have a role in regulation of immune system.
Histamine exhibits a wide variety of both
physiologic and pathologic functions and this
include:
1-
An important but limited role as a chemical
mediator of hypersensitivity reactions.
2-
A major role in the regulation of gastric acid
secretion.
3-
A role as a neurotransmitter in the CNS.
Histamine has no therapeutic application.
The compound is mainly used
1-
as
a positive control in the allergy skin
testing.
2- a diagnostic agent to test the secretory
action of the stomach.
Histamine H1- Receptor
Antagonists
Histamine H1- Receptor Antagonists
• H1-
antagonists
are
the
drugs
that
competitively inhibit the action of histamine
on the tissues containing H1-Receptors.
No
reaction
histamine
Drug
Drug
H1 receptor
H1 receptor
Competitive inhibition
• The H1-antagonists are commonly subdivided into
two broad groups:
The
first
generation
or
classical
antihistamines (sedating)
The second generation or (non sedating)
antihistamines.
Structure Activity Relationship (S A R) of the first
generation antihistamines
Ar
R
X
-
(CH2)n N
R-
Ar
Connecting atom
C.chain
Terminal nitrogen or
tertiary amino moiety
1-
connecting atom X
C O
X=
C O
CH2CH2 N
Aminoalkyl ether or ethanolamine dr.
C CH2CH2
N
Propylamine dr.
X=
C
C
N
X=
CHCH2
CH2CH2 N
N
Ethylenediamine dr.
N
Ar
R
X
(CH 2)n N
-
Ar
R-
2- The carbon chain of typical H1–antagonists consists
of two or three carbon atoms.
3- The terminal nitrogen atom is a simple dimethyl
amino moiety. However, it may be a part of a
heterocyclic structure as in (piperazine, pyrrolidine ,
piperidine, imidazole…….).
H3C
N
N
Triprolidine
4-
Ar
and
Ar`
are
aryl
groups,
including
phenyl,
substituted phenyl (specially with halogen in para
position) and heteroaryl such as 2-pyridly. The two
aryl moieties must be non coplanar to each other for
optimal
interaction
with
H1
receptor.
The
two
aromatic systems may be linked as in the tricyclic
antihistamines.
X
Characters of first generation
antihistamines
1- They have high lipid solubility so, they can
penetrate BBB blocking central H1 receptors and
some CNS receptors.
Sedation, dizziness.
2- They contain the basic pharmacophore required
for binding to muscarinic as well as adrenergic
and serotonergic receptors
overlaping
actions
different pharmacological actions.
*****
A- Amino alkyl Ethers
(Ethanolamines).
R--
Ar
H2 H2
C O C C
Ar
R
N
R-
1- Diphenhydramine HCl (Benadryl)
2
1
CH O CH2CH2 N
CH3
CH3
HCl
2-(Diphenylmethoxy)-N,N dimethylethylamine HCl
• It is used in the treatment of urticaria, seasonal
rhinitis, and some dermatoses.***
• It is used as a sleep aid product. ***
Synthesis
HO
Br
N
CH3
CH O CH2CH2 N
CH3
CH3
Na2CO3
HCl
Metabolism
Question?
CH3
2
1
CH O CH2CH2 N
CH3
CH3
HCl
B- Propylamine derivatives
1- Saturated dr. (pheneramines)
2- Unsaturated dr. (Olefinic)
open chain
dr.
Cyclic analogues
R
Ar
CH
-
Ar
CH2CH2
N
R-
1- saturated dr.
A- chlorpheniramine Maleate
Cl
1
CH
2
2
CH2CH2 N
N1
CH3
.
CHCOOH
CHCOOH
CH3
2-[ p-chloro-α-[ 2-dimethylaminoethyl ] benzyl] pyridine
maleate.
• Insertion of a halogen into the para position of
the phenyl ring increases potency and duration.
D optical isomer with S absolute configuration is
more active ( dexchlorpheneramine maleate)
2- unsaturated dr.
A- open chain dr.
Triprolidine Hydrochloride
H3C
(E)-2- [ 1-(4-methylphenyl)3-(1Pyrrolidinyl) 1-propenyl] pyridine.
H
3
2 1
2
N
Cl-
N1
 E (trans geometric isomer in which the methylpyrolidinyl
group is trans to the
2- pyridyl group) is more active than
the Z (cis) isomer.
• N.B. adding polar group……..as 2-propenoic acid ……second
generation (acrivastine).
B- Cyclic analogue
Dimethindene maleate (fenistil)
1
1
2
1
2
CH2CH2
3
2 CH
H3C
2
CH3
CHCOOH
N
.
CH3 CHCOOH
N
1
2- [ 1-[2-(2-dimethylamino) ethyl] indene-3-yl]ethyl]]
pyridine maleate.
 The potent antihistaminic activity resides mainly in
the levorotatory isomer.
c- Ethylenediamines
The earliest series of H1-antagonists
Characterized by high CNS side effects and
lower anticholinergic and antiemetic effects
R
Ar
N
-
Ar
CH2CH2
N
-
R
E-Tricyclic ring system
1-Phenothiazine
2- phenothiazine analogues
(Cycloheptane and cycloheptene dr.)
S
N
R1
CH2CH(CH2)n
R
N
R2
1- Promethazine HCl [ phenergan]
1
9
2
S
3
10
4
8
7
6
N
CH3
2 5
1CH2CH N
CH3
3 CH3
(±)10-[2-(Dimethylamino)propyl ] phenothiazine.
 It is the parent member of this series .
 It forms HCl salt with the more basic nitrogen ?
 In addition to its antihistaminic action, it has antiemetic,
anticholinergic and sedating effects
Preparation of Promethazine HCl
S
S
N
Fusion
N
H
H
ne
e
u
l
To
/
NH 2-HCl
a
N
Cl
Promethazine
H2 H
C C
CH3
N
CH3 CH3
Phenothiazine analogues 1-Pimethixene
5
10
6
S
7
9
8
4
3
2
4
1
1
N
CH3
1-methyl-4-[ 9H-thioxanthen-9-ylidene]piperidine
1- It is an example for thioxanthene derivatives as potent H1
antagonist.
2- It is an example for the bioisosteric replacement
of the nitrogen of phenothiazine nucleus by an SP2 carbon atom.
2- Cyproheptadine HCl (periactin)
1
a
d
2
b c
5
4
3
4
1
4-(5H-Dibenzo [a,d] cyclohepten-5-ylidene)-1-
N
methylpiperidine
H3C
• It is an example for the bioisosteric replacement of the
nitrogen of phenothiazine nucleus by an SP2 carbon atom
and the sulphur atom is replaced by an isosteric vinyl
group.
• This compound can be used as an appetite stimulant and
it
exhibits both H1-antagonist and antiserotonergic
activity.
S
S
N
CH3
CH2CH N
CH3 CH3
Promethazine
pimethixene
N
CH3
N
Azatidine
N
CH3
Cyproheptadine
N
H3C
O
S
Ketotifen (Zaditine)
N
CH3
1- It is structurally analogous to cyproheptadine.
2- It is a dual acting antihistaminic which acts as potent
H1-antagonist and and mast cell stabilizer (it inhibits the
release of the mediators which are involved in the allergic
reaction)
3- It is used in prophylaxis of asthma