Stereochemistry

1. STEREOCHEMISTRY
Qudsia Rehaman 606
Mutayyba Fatima 608

2. Stereochemistry
 Stereochemistry is defined as the study of the
three-dimensional structure of molecules.
OR
 A branch of chemistry that deals with the
spatial arrangement of atoms and groups in
molecules.

4. Stereoisomers
 Stereoisomers are molecules that contain the
same number and kinds of atoms, the same
arrangement of bonds, but different three-
dimensional structures; in other words, they
only differ in the three-dimensional
arrangement of atoms in space.

5. Geometric isomerism
 Geometrical isomerism is a form of
stereoisomerism describing the orientation of
functional groups within a molecule.
 When two substituents of higher priority are on
the same side of the double bond, this isomer
is given the designation of cis or Z.
 When the substituents are on opposite sides,
the designation is trans or E.

6.  Example:
 The histamine H1-receptor antagonist
triprolidine. The E-isomer of triprolidine is more
active both in vitro and in vivo, indicating that
the distance between the pyridine and
pyrrolidine rings is critical for binding to the
receptor.

7. Enantiomers
 Enantiomers are pairs of molecules for which
the three-dimensional arrangement of atoms
represents nonsuperimposable mirror images.

8. Examples

9. Examples
 R forms – therapeutically active (sedation)
 S forms _ teratogenic

10. Diastereoisomers
 Diastereoisomers represent all of the other
stereoisomeric compounds that are not
enantiomers.
 Thus, the term “diastereoisomer” includes
compounds that contain double bonds
(geometric isomers) and ring systems.

11. Diastereoisomers

13. PHARMACOKINETIC &
PHARMACODYNAMIC
STEREOSELECTIVITY
 Many drugs used in clinical practice contain
one or more chiral centers. These chiral drugs
are often used therapeutically either as pure
stereoisomers or as a racemic mixture. The
three dimensional interaction of two
enantiomers with a macromolecule, such as
an enzyme or receptor, to form diastereomeric
complexes may result in chiral recognition and
significant differences in pharmacokinetic
processes as well as the pharmacodynamics

14. PK parameter Examples
Absorption 1. L-Methotrexate is better absorbed than
D Methotrexate.
Vol. of distribution 1. S-Warfarin has lower Vd than R-
Warfarin.
2. Levoceterizine has smaller Vd than its
dextroisomer.
Metabolism S-warfarin is more potent and metabolized
by ring oxidation while R- Warfarin is less
potent and metabolized by side chain
reduction and have delayed metabolism.
Half-life S-warfarin= 32 hours; R-warfarin= 54
hours

16. Stereochemistry and Biological
Activity
 Easson – Stedman hypothesis
 In 1886, Piutti ; reported different physiologic
actions for the enantiomers of asparagine, (+)
asparagine having sweet taste and (-) asparagine
a bland one. This was one of the earliest
observation that enantiomers can exhibit
differences in biological action.
 In 1933, Easson-Stedman reported that
differences in biological activity between
enantiomers resulted from selective reactivity of
one enantiomer with its receptor. They postulated
that such interactions require minimum
three- point fit to receptor. If the molecule is
unable to properly fit into the receptor and ,
therefore , cannot ‘trigger’ the action.

18. 1)Pharmacological actions :
 Quinine - antimalarial property quinidine (d-
isomer) - antiarrhythmic
 l sotalol - β blocking action d sotalol has
antiarrhythmic action.

19. 2)Therapeutic and adverse
effects
 R thalidomide - sedative S thalidomide
causes teratogenic effect.
 D-ethambutol - to treat TB
L ethambutol causes blindness.

20. 3) Efficacy
 S (-) carvedilol is 100 times more potent
as β blocker than R (-) carvedilol. ( α
receptor blocking action is equipotent)
 S timolol is more potent β receptor
antagonist than R timolol but both reduce
intra ocular tension to same extent.

21. 4) Drug interaction :
 2 stereoisomers can compete for binding to
the same receptor. Eg. S methadone
antagonizes respiratory depressant action of R
methadone.

22.  If the 2 isomers are agonist & antagonist
racemic mixture acts as partial agonist
 Eg. Picendol (Opioid analgesic drug): (+) (3S,
4R) enantiomer - pure agonist (-) (3R, 4S)
enantiomer - pure antagonist (+) (3RS, 4RS)
racemic mixture - partial agonist

23. References:
 Pharmacological Significance of
Stereoisomerism.. Journal of Mahatma Gandhi
Institute of Medical Sciences. 15. 21-26. 5.
Scott, A. K. (1990).
 Stereoisomers in Clinical Pharmacology. Drug
Information Journal , 24 (1), 121–123
 Foye’s principles of medicinal chemistry