1. CHIRAL
pharmacology
By :-
Swati datta
Pharmacology
(M.Pharm,Ist year)

2. RECOGNITION OF CHIRALITY
 Chirality is the fundamental property of
3 –dimensional object.
 Chiral chemistry was identified by Lowis pasteur
when in1948,for the first time seperated the 2-
isomers of sodium potassium tartarate.
• He found that the two isomers were identical in
physiochemical properties but different in their
ability to rotate plane polarized light.

3. WHY STUDYING STERIO CHEMICAL
FEATURES IS IMPORTANT
 Biological Activity may reside in only one of the stereoisomer.
 Stereoisomer's may show essentially similar qualitative And
quantitative activity.
 Isomer may exhibit similar qualitatively but different quantitatively
activities.
 Isomer may show distinct pharmacological activity.

4. CHIRALITY
• Property of a compound whose molecules are not super imposable
on their mirror images.
• Chirality = Handedness.
• Necessary condition for existence of enantiomers.

5. • Same molecular formula, same functional groups.
• Differ in the way atoms are oriented in 3 dimensions.
STEREOISOMERS
ASYMMETRIC CARBON ATOM
• Carbon atom to which 4 different atoms
or groups are attached.
Cl
F
Br
H

6. The Two Types of Stereoisomers
 Geometric isomers
 Optical isomers

7. Geometric Isomers
Cis (on the same side) Trans (across/opposite sides)
 Cis-2-butene
 Molecular Formula- C4H8
 Structural Formula-
CH3CHCHCH3
 Trans-2-butene
 Molecular Formula- C4H8
 Structural Formula-
CH3CHCHCH3

8. Geometric Isomers and Drugs
 Because geometric isomers have different chemical
and physical properties, they act differently as drugs in
our bodies as well.
Example :
•cis-platin used for chemotherapy - it can
enter cancer cells and interact with DNA
•Trans- platin - not active

9. Optical Isomers
Optical isomers
 have a chiral center
 non-super imposable mirror
images

10. Optical Isomers Terminology
Chiral: if a molecule is chiral ( or displays chirality) this
means the molecule has two optical isomers
Chiral centre: the central carbon in an optical isomer with
four bonds each attached to a different group.
Enantiomer: another name for a molecule that is found in
optical isomers. For example, ibuprofen has a two
enantiomers, a left rotating enantiomer and a right
rotating enantiomer.
Racemic mixture: A mixture of 50% left rotating and 50%
right rotating optical isomers

11. ENANTIOMERS
• Stereoisomers that are mirror images of each other.
• Molecule and mirror image cannot be superimposed into each
other even after twisting and turning them.
• Identical physical and chemical properties
• Dextrorotatory ("+" / “d” form) - clockwise direction.
• Levorotatory ("-“ / “l” form) - anti-clockwise direction.

12. DIASTEREOMERS
• Stereoisomers that are not mirror images of each other.
• Similar chemical properties but different physical
properties.
• Is an equimolar solution of the two enantiomers.
• Shows no optical rotation.
RACEMATE

13. R/S SYSTEM
a = 1; b = 2 ; c = 3 ; d = 4
• Priority of an atom is determined
by its atomic number
• Order of substituents going from
highest to lowest priority.
• Clockwise – R (rectus).
• Anticlockwise – S (sinister).
• Unless established experimentally no idea whether (+) or (-)
rotation is associated with R or S configuration.

14. Arthur r. Cushny & “ChirAl”
Pharmacology
1866 - 1926
• (-)-Hyoscyamine almost exactly twice as
active as atropine [( )- hysocyamine]
(1904).
• (-)-Adrenaline twice the potency of ( )-adrenaline as a
vasoconstrictor (1908). (-)-enantiomer 12-15 fold more potent
than (+)-adrenaline on sympathetic vessels (1909).
• Biological Relations of Optically Isomeric Substances (1926).

15. Cushny & “ChirAl” phArmACology
 Believed that the “receptor” was chiral and combined with the
enantiomers of the drug to produce diastereoisomeric drug –
receptor complexes.
 “---- difference in action lies not in the facility with which the
chemical combination is formed, but in the physical
characteristics of the resultant compound” (Cushny, 1926).

16. STEREOPHARMACOLOGY
• Affinity of a drug for a specific receptor and its intrinsic
activity are related to its chemical structure.
• Drug – receptor interactions are stereo selective.
• Minor changes in drug molecule structure.
• Major changes in pharmacological properties.

17. Why do we care about this subtle form of
stereoisomerism?
 Biomolecules (sugars, amino acids, DNA,
proteins, steroids) are chiral
– Proteins are built from L-amino acids, which implies
that enzymes – the catalysts of nature - are chiral
– Also, receptors (drug, taste, biopharmaceuticals,
agrochemicals) are chiral and the natural ligand to a
receptor is often only one specific enantiomer
– This is why mirror image molecules can have radically
different activities (effectivity, toxicity, taste) in the
body.

18. Right-handed and left-handed molecules
interact with living systems in very different
ways and results for example in:
olfactory sensors are chiral
(R)
CH3
O
H
(S)
CH3
HH2C
CH3
CH2
H3C
O
Mirror plane
(R) Spearmint oil (S) caraway oil
− Different
smell

19. CHIRAL DRUGS IN BIOLOGICAL SYSTEMS

20. Biological
Discrimination

21.  1987
• 57% marketed drugs were chiral.
• 2% single enantiomers.
 2006
• 80% drugs approved by the FDA were chiral.
• 75% single enantiomers.
CURRENT STATUS OF CHIRAL DRUGS

22. − In 2000, 40% of drugs on sale in the US were
single enantiomer-based.
− In 2004, about 80% of drugs entering market
are single enantiomer variants
− FDA now requires information about the
structure and activity of each isomer present
in a racemic mixture of a new medication.

23. What sparked the change????
• 1987 – change in FDA regulations.
• Inclusion of information on the enantiomer composition of
chiral compounds in new-drug applications.

24. THALIDOMIDE
• One asymmetric carbon atom, exists as 2 enantiomers
• S-Enantiomer → sedative
• R-Enantiomer Teratogen
Phocomelia
S
thalidomide
R thalidomide
teratogen

25. CHIRAL INVERSION
• Unique metabolic pathway.
• Enzymatic or non-enzymatic.
• Involves unidirectional conversion of one enantiomeric
form to another.
R → S

26. CHIRAL SWITCH
• Development of a single enantiomer from a previously
marketed racemate.
• Resulted in a number of agents being re-marketed as
chiral drugs.
• Same or similar therapeutic indications.
• Novel indications for old compounds.

27. β2 ADreNErgic recePTOR AGONIST
 Salbutamol
• Salbutamol →Mixture of (R)-salbutamol and (S)-salbutamol
• Levosalbutamol is the (R)-enantiomer → active
bronchodilator.
Racemic and (S)-Salbutamol
• Induce airway hyper responsiveness.
• Increase sensitivity to allergen
challenge.
• Inhalation of levosalbutamol→ greater bronchodilatation than the
equivalent dose of the racemate.
R SR
S

28. CALCIUM CHANNEL BLOCKER
 Verapamil
• (S)-verapamil : vasodilating , cardiac antidepressant properties.
• (R)-verapamil : a vasodilating drug.
• Verapamil blocks the P170 glycoprotein.
• Interaction is non stereoselective.
• Partially reverse multiple drug resistance of cancer cells.
• R-verapamil might be expected to be more beneficial.

29. S-AMLODIPINE
• S-Amlodipine → active calcium channel blocker.
• R-Amlodipine → inactive as calcium channel blocker.
• Mainly responsible for peripheral edema.
• Treatment of hypertension.
• S-Amlodipine is effective at half the
dose of racemate.
• Incidence of peripheral oedema is
negligible.

30. • Treatment of normotensive angina patients.
• S-Amlodipine is effective at half the dose of racemate.
Cont..

31. LOCAL ANAESTHETIC
Levobupivacaine
• Cardiotoxicity of the drug : R-enantiomer.
• Levobupivacaine - „S‟ enantiomer of Bupivacaine.
• Moderately more potent.
• Significantly reduced negative inotropic effect .
Levobupivacaine is less cardiotoxic.

32. SELECTIVE SEROTONIN REUPTAKE
INHIBITOR
Escitalopram
• S-enantiomer of Citalopram.
• Doses that show improvement in depressed
patients.
10 mg / day – „S‟ enantiomer
40 mg / day – racemate
• Other advantages of Escitalopram.
• Faster onset of action.
• Reduction in side effects.
• Improved tolerability profile.
S R

33. ANORECTIC AGENT
 Sibutramine
• Activity of racemic sibutramine – active metabolites.
• R-sibutramine metabolite are
More potent in the inhibition
of monoamine uptake.
Greater anorexic potency.
Under evaluation for treatment of depression.
Single enantiomer of metabolite - treatment of both obesity
& depression.

34. NON-STEROIDAL ANTI-INFLAMMATORY
DRUG
 Dexibuprofen
• Inhibition of cyclooxygenase activity – „S’ enantiomer.
• 60% of R enantiomer undergoes chiral inversion to the
active S-enantiomer.
• chiral Dexibuprofen (1200 mg daily) was better than
racemate (2400 mg daily).
• Highly effective NSAID.
• Low adverse effect profile .
**

35. ADVANTAGES OF CHIRAL DRUGS
• Chiral drug is a single agent instead of a mixture of
two distinct drugs.
• Simplifies the interpretation of the Basic Pharmacology.
• Greater selectivity for their biological targets improved
therapeutic indices and reduced adverse effects.
• Longer or shorter duration of action - more appropriate
dosing frequency.
• Decreased inter individual variability.

36. SOME DRUGS ARE BETTER AS
RACEMATES
 BLOCKERS
• blockers currently used contain at
least one chiral center.
• Most are marketed as racemates.
-

37.  Labetalol
• Two chiral centres ; four stereoisomeric forms.
• R, R-isomer : b -blocking property
• S, R-isomer : a -blocking property
• Remaining isomers : inactive
• Dilevalol ( R,R-isomer ) – elevated liver function tests.
• Chiral dilevalol was withdrawn.