The document discusses the importance of stereochemistry in understanding biologically significant molecules such as drugs, proteins, and nucleic acids. It covers key concepts including chirality, isomers, stereoisomers, and the impact of stereochemistry on pharmacokinetics and pharmacodynamics of drugs, highlighting how different enantiomers can exhibit varied biological effects. It also presents examples of stereoselectivity in drug absorption, distribution, metabolism, and elimination based on differences between enantiomers.

1. STEREOCHEMISTRY
&
DRUGACTION
PREPARED BY : AZMIN M MOGAL (M.PHARM SEM -1)
GUIDED BY : Dr. UTTAM MORE
DEPARTMENT : PHARMACEUTICAL CHEMISTRY
( ADVANCED MEDICINAL CHEMISTRY )
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2. stereochemistry
AA A branch of chemistry that
deals with the spatial
arrangement of atoms and groups
in molecules
"stereo”- means “three-dimensionality’’
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3. • A clear understanding
of stereochemistry is crucial
for the study of complex
molecules that are
biologically important, e.g.
proteins , carbohydrates ,
nucleic acids and drug
molecules (especially in
relation to their behaviour
and pharmacological
actions)
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4. IMPORTANT DEFINITIONS
CHIRALITY: Many objects around us are handed. For
example, our left and right hands are mirror images of
each other, and cannot be superimposed on each
other
ISOMER: An isomer is a molecule with the same
molecular formula as another molecule, but with a
different chemical structure. That is, isomers contain
the same number of atoms of each element, but have
different arrangements of their atoms
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5. STEREOISOMERS : Compounds with the same molecular connectivity but
differ in the spatial arrangement of their constituent atoms or groups.
ENANTIOMER : Greek word: enantio : opposite
merons : parts
Stereoisomers with non superimposable mirror images.
DIASTEREOMER : Diastereomers are stereoisomers that are not mirror
images of one another and are non-superimposable on one another.
Stereoisomers with two or more stereocenters can be diastereomers.
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6. • PHARMACOKINETIC:
the study of the bodily
absorption,
distribution,
metabolism, and
excretion of drugs
(ADME) – What body
does to the drug
• PHARMACODYNAMIC:
What the drug does to
the body
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8. Stereoisomers
1. Configurational isomer :
# Geometric isomers :
(a) cis & trans system / E & Z system
# Relative configuration / Fischer projection ( L & D configuration)
# Absolute configuration (R & S configuration)
2. Conformational isomer / rotamers :
# Anti & gauche conformation / staggered & skew conformation
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9. L & D CONFIGURATION
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10. EXAMPLE OF
L & D
SYSTEM
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11. R & S CONFIGURATION
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13. CONFORMATIONAL ISOMERS
• CONFORMATIONAL ISOMERS are the type of stereoisomerism ; Stereoisomers
have the same functional groups and connectivities , they differ only in the
arrangement of atoms and bonds in space The different spatial arrangements
that a molecule can adopt due to rotation about carbon-carbon single
bonds are known as conformations
• Different conformations also are called conformational isomers /
conformers / rotamers.
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14. 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.
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15. Pharmacokinetics stereoselectivity
1.Absorption
* Passive intestinal absorption
* Carrier transporter stereoselectivity
2.Distribution
* Protein binding
* Tissue distribution
3.Metabolism
* first pass metabolism
* Phase I and phase II metabolism
4.Elimination
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16. Absorption and stereoselectivity
Passive intestinal absorption
For the majority of racemic drugs, absorption appears to be by
passive diffusion , provided no stereoselectivity.
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17. Carrier mediated
transporter
Stereoselective
intestinal transporter is
the main cause for
marked differences in
the oral absorption of
enantiomers.
L-methotrexate have 40
fold higher Cmax and
AUC than
D-methotrexate.
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18. Distribution
Protein binding
Stereoselective plasma protein binding could influence distribution and
elimination because the major determinant of drug distribution and elimination
is protein binding.
The enantiomers may display different magnitudes of stereoselectivity between
the various proteins found in plasma
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19. Ex// the R-propranolol binding to albumin is greater than S-propranolol and the opposite is
observed for 1 -acid glycoprotein.
* Highly albumin bound
* Less potent
* Highly metabolized
* Low plasma concentration
*highly bound to AAG
available as unbound
* 40-100 time more potent
*Less metabolized
*High plasma concentration 19

20. Metabolism
Stereoselective drug
metabolism is commonly
observed in vitro for
racemic drugs and can
results in substantial
differences in the vivo
plasma concentration –time
profiles between
enantiomers due to
stereoselective
bioavailability or drug
disposition.
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21. Phase I and phase II metabolism
The magnitude of stereoselectivity depends on the metabolic
pathways involved drug metabolism.
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22. some time the two isomers compete with each other to bind the enzyme
binding site, this result in inhibition the metabolism of the one enantiomer.
Ex//propaphenon
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23. EFFECT ON PHARMACOKINETIC OF SOME STEREOACTIVE DRUGS
PK
parameter
Examples
Absorption 1. L-Methotrexate is better absorbed than D-
Methotrexate
2. Esomeprazole is more bioavailable than
racemic omeprazole
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
Half-life S-warfarin= 32 hours; R-warfarin= 54 hours 23

24. PHARMACODYNAMICS
• 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.
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25. PHARMACODYNAMIC
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26. Easson-Stedman Hypothesis
•The Easson-Stedman Hypothesis states that
the more potent enantiomer must be
involved in a minimum of three
intermolecular interactions with the
receptor surface .
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27. EXAMPLE ; Drug receptor interaction of (R) – (-)-epinephrine ,
(S)-(+)- epinephrine , and N- methyl dopamine.
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28. REFERENCES
• Thomas L. LEMKE , David A. WILLIAMS , “FOYE’S PRINCIPLES OF MEDICINAL
CHEMISTY ’’ , (south Asian edition) sixth edition, stereochemistry, stereochemistry
and Biological Activity , Lippincott Williams & wilkins ,Wolters Kluwer Indian
publication , 2011, 30-45, 51.
• YOUTUBE :
cis & trans configuration; link ; https://www.youtube.com/watch?v=-38re1DSIv4
R & S system ;link;
https://www.youtube.com/watch?v=KoAnGRlCG_M&list=PLaySzQJTCO1nsM3ItT8irQ
650tYgjHk6i&index=3
Anti & gauche conformation ; link;
https://www.youtube.com/watch?v=BpIww4loV9M
• Jerry March , “ ADVANCED ORGANIC CHEMISTRY ” , FOURTH EDITION , published
by John Wiley & sons( Asia) , 2005 , 94 & 127.
• Wikipedia & other internet sources.
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