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Stereochemistry
The stereochemistry of both the receptor site & the drug molecule helps determine the nature &
efficiency of the drug-receptor interaction. Isomers are 2 or more compounds, with the same
molecular formula, but have different configurations. They usually differ in chemical, physical or
pharmacological properties.
Stereoisomers can be divided into 3 main groups:
o Optical isomers,
o Geometric isomers,
o Conformational isomers.
I. Optical Isomers:
Contain at least 1 asymmetric, or chiral, carbon atom (a carbon atom which is covalently bonded to 4
different substituents). Each asymmetric carbon can exist in 1 of 2 non-superimposable isomeric forms.
The 2 enantiomers of 2-hydroxybutane.
The chiral carbon is bonded to 4 different
groups. The structures shown are mirror
images that cannot be superimposed.
1. Enantiomers (Optical antipodes):
o Are optical isomers that are mirror images (have at least 1 asymmetric carbon), not superimposable.
o Enantiomers have identical physical & chemical properties except that one rotates the plane
of polarized light in a clockwise direction (dextrorotatory, designated D or +) & the other in a
counter-clockwise direction (levorotatory, designated L or -).
o An equal mixture of D and L enantiomers is called a racemic mixture & is optically inactive.
o
Enantiomers can have large differences in potency, receptor fit, biologic activity, transport &
metabolism. E.g., levorphanol has narcotic, analgesic, & antitussive properties, whereas its
mirror image, dextrorphanol, has only antitussive activity.
o Mutarotation: is a change in the optical rotation of a solution of an optically active compound
(common in carbohydrate solutions).
H – C – OH
HO – C – H
H–C–H
H–C–H
N
N
H
CH3
Dextro (+)
H
CH3
Levo (-)
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2. Diastereomers:
o Are stereoisomers, which are neither mirror images nor superimposable.
o A drug must have at least two chiral centers in order to exist in diastereomers.
o Unlike enantiomers, in which all stereochemical centers are opposite, diastereomers have
some stereochemical centers that are identical & some that are opposite.
o Diastereomers possess different physicochemical properties &, thus, differ in properties, such
as solubility, volatility, & melting points.
o Ephedrine has 2 assymetric centers & 4 isomers, there are 2 pairs of optical enantiomers:
i. 2 pairs are designated ephedrine (levo & dextro) (mirror images).
ii. The 2 other pairs are designated pseudo-ephedrine (levo & dextro) (mirror images).
iii. However, ephedrine & pseudo-ephedrine are diasteriomers (not mirror images).
H – C – OH
CH3 – HN – C – H
H O– C – H
H – C –NH – CH3
CH3
CH3
Dextro (+)
Levo (+)
Pseudo-ephedrine
HO – C – H
H – C – OH
H – C –NH – CH3
CH3 – HN – C – H
CH3
CH3
Levo (+)
Dextro (+)
Ephedrine
3. Epimers:
o Are a special type of diastereomers because all epimers are also diastereomers; however, the
opposite is not true.
o Epimers are compounds that are structurally identical in all respects except for the
stereochemistry about one chiral center.
o The process of epimerization (in which the stereochemistry of one chiral center is inverted) is
important in drug degradation & inactivation.
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II- Geometric Isomers (cis-trans isomers)
Occur as a result of restricted rotation around a chemical bond, owing to double bonds (or rigid ring
systems) in the molecule.
o Cis-trans isomers are not mirror images & have different physicochemical properties &
pharmacologic activity.
o Cis means that both 2 groups are fixed around the double bond so that they are both on the
same side of the molecule. (Cis = Z).
o Trans means that both 2 groups are fixed around the double bond so that they are on opposite
sides of the molecule. (Trans = E).
o Because the functional groups of these isomers are separated by different distances, they
generally do not fit the same receptor equally well. E.g., cis-diethylstilbestrol has only 7% of
the estrogenic activity of trans-diethylstilbestrol.
The presence of the
double bond allows for
the formation of cis &
trans isomers
CH3 (CH2)7 CH
HOOC (CH2)7 CH
Oleic acid (Cis configuration - Z)
CH3
CH3
CH3 (CH2)7 CH
CH (CH2)7 COOH
Eliadic acid (Trans configuration - E)
CH3
C=C
H
H
C=C
H
Cis 2 butene (Z)
H
CH3
Trans 2 butene (E)
III- Conformational Isomers (Rotamers or Conformers)
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o Are non-superimposable orientations of a molecule which result from the rotation of atoms
about one or more single bonds.
o Ethane has 2 conformational isomers:
H
H
H
H
H
H
H
H
H
H
H
H
Staggered
Eclipsed
o Cyclo-hexane exists in 2 conformers:
Boat
Chair
o Almost every drug can exist in more than one conformation, & this ability allows many drugs
to bind to multiple receptors & receptor subtypes. E.g., the trans conformation of
acetylcholine binds to the muscarinic receptor, whereas the gauche conformation binds to the
nicotinic receptor.
The trans & gauche conformations
of acetylcholine occur as a result of
rotation about the carbon – carbon
single bond.
trans
gauche
IV- Bioisosteres
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o Are molecules containing groups that are spatially & electronically equivalent &, thus,
interchangeable without significantly altering the molecules' physicochemical properties.
o Isosteric replacement of functional groups can increase potency, decrease side effects,
separate biologic activities, & increase the duration of action by altering metabolism.
o Additionally, isosteric analogs may act antagonistically to the parent molecule.
 Procainamide, an amide, has a longer duration of action than procaine, an ester,
because of the isosteric replacement of the ester oxygen with a nitrogen atom.
 Alloxanthine is an inhibitor of xanthine oxidase. It is also an isostere of xanthine, the
normal substrate for the enzyme.
S
N
CH2 CH2 CH2N
S
O
CH3
CH3
Phenothiazine ring
CH3
CH2 CH2 CH2N
CH3
Thioxanthene ring
Homologs: When 2 compounds differ only in the length of side chain.
S
S
N
CH3
N
CH3
CH2 CH2 N
CH2 CH2 CH2 N
CH3
CH3
N.B. Bioisosters & homologs are not optical isomers.
Tautomerism: Keto – Enol form (e.g. Uracil, purine / pyrimidine).
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