Stereochemical Aspects of Drugs
Jutti Levita
for Molecular Pharmacology and Medicinal Chemistry
References
Korolkovas, A., 1970, Essentials of Molecular
Pharmacology: Background for Drug Design,
Wiley-Interscience
STEREOCHEMISTRY 3
CONSIDERATIONS
Most natural organic products, the essential products of
life, are asymmetric.
This established perhaps the only well marked line of
demarcation that can at present be drawn between the
chemistry of dead matter and the chemistry of living
matter.
Louis Pasteur, circa. 1848
The receptor theory of drug action implies that
the pharmacological properties of a compound
are dependent not only on the nature and properties of the
constituent groups within the molecule
but also in the way in which these groups are distributed in space
[E.W. Gill]
Fisher projection:
The tetrahedral atom is
viewed perpendicularly to
an edge formed by
connecting two of its
ligands.
The convention is that the
two vertical bonds in the
projection are pointing
behind the plane of
projection (plane of paper
sheet), and the two
horizontal bonds are
pointing towards the
viewer.
Wedge projection:
It is obtained by viewing the
tetrahedral center
perpendicularly to the plane
formed by three atoms. One of
the remaining atoms is oriented
behind the plane of projection
(dashed bond), one towards
the viewer (boldface bond).
Note that, in contrast to Fisher
projection, the rotation of the
wedge projection about axes
perpendicular or coplanar with
the plane of projection does not
change anything.
Newman projection:
The molecule with two tetrahedral centers is viewed along the C-C axis. The
atom in front is represented as a three-way branch, the atom in the back as a
circle with three outgoing bonds. This projection is most useful inconsideration of
steric relation between ligands linked to adjacent tetrahedral centers and is most
popular.
Sawhorse projection:
The C-C bond is viewed at an angle. The atom shown on the left of the
projection is also the one in the front. This projection is difficult to use with
acyclic molecules but is most popular for representation of cyclic molecules
e.g. saturated six-membered rings.
Haworth projection:
The difference in the pharmacological activity of many
stereoisomers is the best evidence for the existence of a
receptor due to 3 factors:
1. Differences in the distribution of isomers in the body
2. Differences in the properties drug-receptor
interactions
3. Differences in the adsorption of isomers to a
complementary receptor surface
Conformation of Drugs
Conformer
The boat is the transition state between two twist conformers
during the ring flip. It is strained by eclipsed interactions along
each side, and a strong van der Waals repulsion between the
two hydrogens that project toward the center of the ring.
Staggered and eclipsed conformations coexist in ethane. They are transformed
into one another with ease and speed, through rotation around C-C bond.
Influence of Stereochemistry
on Pharmacological Activity
Bacteriostatic activity of 9-
aminoacridine is directly related to a
minimal planar surface of about 38
2.
Removal of one of the external rings
or substitution by a saturated (or
bulkier) ring results in complete loss
of activity.
In silico screening reveals structurally diverse, nanomolar
inhibitors of NQO2 that are functionally active in cells and
canmodulate NF-B signaling.
Nolan, K.A., Dunstan, M.S., Caraher, M.C., Scott, K.A.,
Leys, D., Stratford, I.J.
Journal: (2012) Mol.Cancer Ther. 11: 194-203
Influence of Stereochemistry
on Pharmacological Activity
An antiinflammatory agent such as Ibuprofen has two configurations
(R and S).
However, only S-configuration has
pharmacologic properties.
The demonstration (video) of
superposition between the S and R
configurations indicates that they are
enantiomers. They are
nonsuperposable mirror reflection of
each other.
H H
H3 C H3C
CH3 COOH CH3 COOH
H3 C H3 C
S-Ibuprofen R-Ibuprofen
Inhibits platelet thromboxane Racemizes to the S-form and does
production twice as effectively as does not cause G.I. lesions
the racemate
Influence of Stereochemistry
on Pharmacological Activity
O O
NHCH3 NHCH3
Cl Cl
S-(+)-Ketamine R-(-)-Ketamine
2-4 times more potent than Causes spontaneous motor
R-(-)-ketamine in activity and post-emergent
anaesthesia distress
Influence of Stereochemistry
on Pharmacological Activity
The adrenergic blocking of -
haloalkylamines depends also on the
coplanarity of substituents in the
benzene ring. Phenoxybenzamine
Phentolamine
OH
H H
Adrenaline HO N
CH3
HO
Salbutamol H
OH
H
(Ventolin) HOCH2 N CH3
C
(Anti-asthmatic) CH3
(selective -Blocker) HO CH3
CH3
Propranolol H
(non selective -Blocker) O N CH3
H
OH
-Adrenoceptor
H-Bonding
region Ionic
H-Bonding
region bonding
Van der Waals region
bonding region
H-Bonding
region
-Adrenoceptor
H-Bonding
region
Ionic
H-Bonding bonding
region region
Van der Waals
bonding region
H-Bonding
region
OH
H H
a-Adrenoceptor
HO N
CH3
HO
ADRENALINE
OH
H H
-Adrenoceptor
HO N
CH3
HO
ADRENALINE
OH
H H
HOCH2 N CH3
-Adrenoceptor C
CH3
CH3
HO
SALBUTAMOL
OH
H H
a-Adrenoceptor
HOCH2 N CH3
C
CH3
CH3
HO
SALBUTAMOL
OH
H H
HOCH2 N CH3
a-Adrenoceptor
C
CH3
CH3
HO
SALBUTAMOL
Optical Isomerisms in Drugs
Optical isomers are stereoisomers
in which the arrangements of atoms
or groups is such that the two
molecules are not superimposable.
Geometrical Isomerism of Drugs
Geometric isomers are stereoisomers of the same
structures but with different spatial arrangements of
atoms or groups.
They are not mirror images, but it could be determined
by a restricted rotation within a molecule, either
through double bonds or through rigid or semirigid
systems.
Jutti Levita-Pharmacochemistry Science Group-Faculty of
Pharmacy-Universitas Padjadjaran
34
Olbe et al, Nat Rev Drug Discovery 2:132, 2003
Ephedrine is a sympathomimetic amine that
acts on part of the sympathetic nervous EPHEDRINE
system (SNS). The principal mechanism of
action relies on its indirect stimulation of the
adrenergic receptor system by increasing Ephedrine
the activity of noradrenaline at the post-
synaptic - and -receptors.
The presence of an N-methyl
group decreases binding affinities at -
receptors, compared with norephedrine. On
the other hand ephedrine binds better
than N-methylephedrine, which has an
additional methyl group at the N-atom. Also
the steric orientation of
the hydroxyl group is important for receptor Norephedrine
binding and functional activity.
Jutti Levita-Pharmacochemistry Science Group-Faculty of
Pharmacy-Universitas Padjadjaran
