Antihistamines
Our agonist is Histamine
3
Structure:
1
2
Binding requirements:
Amine (1ry amine, Pka=9, 95 % ionized and 5 %
unionized at physiological PH, cross BBB, sedative,
steering effect) make ionic interaction.
Imidazole ring ( Pka=5.74, not ionized at blood PH)
make H-bond and Pi-Pi stacking.
H1 blockers:
1st generation: sedatives ( 3ry amine, Pka=9, 95 %
ionized and 5 % ionized at physiological PH, cross
BBB, also contain a group that make H-bond and
other that make Pi-Pi stacking)
Many Scaffolds (basic structure):
1. Amino alkyl ethers:
2. Propyl amines:
3. Piperazine:
Ionic
interaction
4. Phenothiazines:
Ionic
interaction
2nd generation: non-sedatives ( this contain a group
that make a H-bond and another one that make Pi-Pi
stacking)
Now the ionic interaction group it's even:
a) 2ndry amine ( Pka=9.8, 99.6% ionized at
physiological PH, don't cross BBB)
OR
b) 3ry amine ( Pka=9, 95 % ionized and 5%
unionized at physiological PH) but it contain
-COOH group in the homologation region ( Pka=4.5,
100% ionized at physiological PH, don't cross BBB).
No certain scaffold so go back to slides and look at the
structures.
H2 blockers:
H-bond
Pi-Pi stacking
Spacer
Ionic interaction
In cimetidine it is guanidine
In famotidine it is guanidine attached to sulfamoyl
ionic
In ranitidine it is nitroketenaminal group
Chain extension with thiol are essential for H2
antagonism
H-bond
spacer
Pi-Pi stacking
Ionic
In cimetidine it is imidazole
In famotidine it is thiazole
H-bond
Pi-Pi
stacking
In ranitidine it is furan
Proton Pump Inhibitors:
Scaffold (basic structure)
Methyl
PYRIDINE
Sulfinyl
Benz imidazole
What are the side effects of PPI's and H2 blockers:
1. GI disturbances ( diarrhea)
Now normal flora is responsible for the control of electrolyte
balance so when you mess-up with PH you lead to
electrolytes' disturbances and diarrhea.
2. Super infection
PH changes may lead to the killing of normal flora so the
space is now available for other microorganisms to occupy.
To overcome these problems: give probiotics or ‫اشرب لبن‬.
3. Vitamin B12 deficiency due to the decrease in absorption (
no intrinsic factor to be absorbed)
To overcome this give Vit B12 supplement oral or injections.
4. Negative Ca++ balance so pain in bone and joints
Why? Ca++ is more absorbed in acidic PH so when we
increase PH ( we decrease acidity) so Ca++ less absorbed.
To overcome this take Ca++ supplement
OR
Don't take the drug with food
OR
Increase intake of Ca++
5. Decrease iron absorption so take supplement.
Cholinergic and Anticholinesterase:
Agonist is Acetylcholine:
Properties:
Permanently ionized so not absorbed orally
Flexible molecule ( so many configuration)
Not selective ( bind to both the nicotinic and
muscarinic receptor)
Not stable ( hydrolyzed by esterase's in the blood
and stomach)
Anticholinesterases prevent the breakdown of acetylcholine
so it has a cholinergic agonist effect.
Go back to slides for more details.
Adrenergic:
Agonists: epinephrine and norepinephrine
β OH
Norepinephrine:
αcarbon
OH on the
aromatic
ring
OH on the aromatic ring: decrease CNS effect but increase
potency.
β-OH in side chain: decrease CNS effect and decrease potency.
Small substituents on N ( like methyl): increase CNS effect but
decrease intrinsic activity.
Disubstituents on N lead to lose of activity.
Methyl on α carbon in the side chain: increase potency and CNS
effect.
Features for Direct acting Sympathomimetic:
Scaffold (basic structures):
1. β phenyl ethyl amine:
Now R2,R5,R6 are H.
a. Amino group is essential for agonist activity must
be separated from aromatic ring by 2 carbon.
Substituents on this amino group affects receptors
selectivity. In general, increase in Bulkiness will
decrease its α receptor agonist and increase βreceptor agonist. (Also make it MAO resistant)
b. If Rα is an alkyl substituents then:
- It make it resistant to MAO.
- Enhance oral effectiveness and CNS activity
- Increase selectivity toward α2 and β2.
c. Replacement of catechol with the resorcinol increase β2
selectivity.(make it resistant to COMT)
d. Replacement of meta OH at R3 position with CH2OH
increase β2 selectivity.( make it resistant to COMT)
e. Removal of para OH at R4 position make it selective to α1
receptor.
2.Imidazoline containing: presence of Imidazoline
make it selective for α
X: optimally it is a single amino or methylene group.
Small alkyl or halogen group (like methyl, chlorine) on aromatic
ring in the two ortho positions enhance activity)
(phenylimino)- imidazolidine derivative ( α2
agonist) example is Clonidine.
Now let's start specifically with each class.
Features for α selectivity:
Imidazoline ring
Note; the type of group attached to the Imidazoline ring
dictates whether an Imidazoline is an agonist or antagonist.
A)2-aralalkylimidazolines : it is a partial agonist for both α1
and α2 receptors.
Example:
B) Imidazoline containing antagonist: these are α1 and α2
antagonist.
α-1 agonist features:
scaffold: β phenyl ethyl amine with no para- OH
on the aromatic ring
example: phenylephrine
α-2 agonist features:
1. (phenylimino)- imidazolidine derivative:
1
2
At position 1, 2 even add 2 Cl or 2 alkyl (like ethyl) to
enhance activity.
2. “Open-ring imidazolidines”. In these compounds, the 2.6dichlorophenyl moiety found in clonidine is connected to a
guanidino group by a two-atom bridge.
Example: Guanabenz, Guanfacine.
3. β phenyl ethyl amine with α-methyl on side chain.
Example: Methyldopa
β-2 agonists features:
1. Add a small group ( methyl group or ethyl group) to the αcarbon side chain.
Example: ethyl norepinephrine
2. Replace catechol ring with resorcinol ring.
Example: metaproterenol and terbutaline.
3. Bulk group on the N( tertiary Butyl instead of H or
methyl).
Example: Bitolterol
4.replace OH on meta position in the aromatic ring withCH2OH.
Example: Albuterol.
α antagonism features:
1. Imidazolines: (reversible inhibitors)
The type of group attached to the imidazoline ring dictates
whether an imidazoline is an agonist or antagonist.
Example: Phentolamine, Tolazoline.
2. β-halo alkyl amine: (Irreversible non selective)
R1
R2
α 1 antagonism features:
SAR: consists of three components:
The quinazoline ring+ the piperazine ring+ and the acyl
moiety.
Quinazoline ring must have an amino group on
position 4 to be protonated in order to bind to
the α receptor.
Piperazine ring ( Spacer) can be replaced with
other heterocyclic moieties (e.g., piperidine
moiety) without loss of affinity.
Acyl chain this is the different part between
agents and affect their pharmacokinetics.
Yohimbanes: This class is comprised of isomeric
indole alkaloids that exhibit different degree of
selectivity towards the α1- and α2-adrenergic
receptors depending on their stereochemistry.
Yohimbine is selective antagonist of the α2- receptor, while
Corynanthine is selective antagonist of the α1- receptor.
β antagonisms features:
scaffold ( basic structure) is
Aryl Oxy Propanol Amine
Now what determine if it selective to β1 or non-selective is
the nature of the aromatic ring and its substituents is the one
that is the primary determinant of b-antagonistic activity.
The aryl group also affects the absorption, excretion, and
metabolism of b-blockers .The nature of the aromatic ring is
also a determinant for the selectivity toward β1- & β2receptors.
( how many substituents on the aryl group and what is the
positions)
To make it selective for β1: make a substituent on para position
without a substituent on meta position. Otherwise, it is non
selective blocker:
Examples:
Non-selective:
β 1 blocker:
Calcium Channel Blocker:
1. 1,4-Dihydropyridine:
2. Phenyl alkyl amine:
Example: verapamil
3. Benzothiazine:
Example: Diltiazem