Kimia Medisinal I(2 SKS)
P6: Hubungan stereokimia dan aktivitas obat
Genap | 2021
Sifat kimia fisika sbg dasar aktivitas obat
Pada proses absorpsi dan distribusi obat
dipengaruhi oleh: sifat lipofilik molekul obat (kelarutan
dalam lemak/air) dan sifat elektronik molekul obat
(derajat ionisasi, suasana pH)
Pada proses interaksi obat dan reseptor
dipengaruhi oleh: tipe ikatan kimia, interaksi hidrofobik, kerapatan elektron, ukuran molekul obat, dan efek
stereokimia sifat sterik dan elektrik molekul obat
Dari kuliah sebelumnya...
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Structure-physiochemical properties:
Water solubility, partition coefficient, …
Stereochemistry biomolecules (reseptors,
enzymes)
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Importance:
In pharmaceutical industries, 56% of the drugs currently
in use are chiral molecules and 88% of the last ones are
marketed as racemates (or racemic mixtures), consisting
of an equimolar mixture of two enantiomers.
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Thalidomide cases
In 1960 in Europe, racemic
thalidomide was given to
pregnant females to cure
morning sickness.
This led to deformations in
babies and neurotoxic effects.
These were due to S-
thalidomide.
R-thalidomide contained the
desired therapeutic activity
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Example:
In biological system there is a preference of a specific
stereoisomer.
Amino acids: 20 amino acids (exc. glycine) have L-
and D- forms, only the L- form is proteogenic
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Example:
Sugars: most sugars (e.g. glucose, fructose) occur
naturally as the D-form
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D and L chirality
Dextrorotary compound: "(+)-" or "d-"
Levorotary compound: "(−)-" or "l-"
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Isomers:
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Example: constitutional isomers
Functional group: Same molecular formula, but
different functional groups,
e.g., n-propanol and methyl
ethyl ether
Positional:Same molecular formula,
same functional groups, but
different positions of
functional groups, e.g., n-
propanol, 2-propanol
O
O
CH3
NH2
NH
CH3
O
OCH2CH
3
3,4-MDA phenacetin
(Ecstasy) (analgesic)
N
CH3
Ph COOEt
N
CH3
Ph
COOEt
Mepiridine
(Analgesic) (not analgesic)
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Example: configurational isomers
Geometric (cis/trans):Same molecular formula, same
functional groups, same
positions, but different
orientation around a double
bond or on a ring.
An important criteria to exhibit
geometric isomerism is that the
isomers cannot be
interconverted through mere
rotation around a single bond.
H
H
OH
OH
H
H
OH
OH
trans-DEC cis-DES
(Estrogenic) (non estrogenic)
H
N
NCH3
Triprolidine (E)
Trans isomer, i.e., E, is 1000-times more
histaminic than cis, Z
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Stereoisomers
Enantiomers: pair of
stereoisomers that are related
to each other as non-super-
imposable mirror image
isomers
Diastereomers: pair of
stereoisomers containing more
than one chiral center and are
not mirror images of each
other
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Enantiomers: non-superimposible mirror images
mirror plane
Lactic acid
from muscle tissue
Lactic acid
from milk
R = Rectus
S = Sinister
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Diastereomers: stereoisomers that are not mirror
images
L-erythrose L-threose
has the R configuration at
C2 and the S configuration
at C3
has both S configuration
at C2 and C3
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Chiral center
Chiral molecules usually contain at least
one carbon atom with four non-identical
substituents.
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Identification of chiral centers
Chiral centers: carbon, nitrogen, phosphorus
N
CH3
O
O
O
O
NCH
3
OMe
OMe
OMe
MeOOMe
OMe
MeO
MeO
Atracurium besylate (neuromuscular blocking agent)
++
**
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Identification of chiral centers
Chiral centers: carbon, nitrogen, phosphorus
OH
OH
OH
NH2
Nor-epinephrine
O O
OH
CH3
OPh
warfarin
N
NOH
quinine
*
*
* * *
*
*
CH3
CH3
CH3
OH
CH3
CH3
cholesterol
*
**
***
**
O
N
H
OHCH
3
OH
9R
6S
5R
13S
14R
morphine
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Identification of chiral centers
Step 1 identify chiral center
Step 2 assign priority:
higher the atomic number, higher the priority
atoms with same atomic number heavier isotope, higher priority
if same priority for immediate atoms, continue down the second atom
double bonds are duplicated; triple bonds are triplicated Step 3 visualize molecule so that the group of lowest priority is directed away
Step 4 draw (or visualize) Newmann projection of the remaining three groups
Step 5 write the priority order 1, 2 and 3; draw (or visualize) an arrow traveling from
123: if the arrow travels clockwise, the chiral center is ‘R’; otherwise it is
‘S’
CH3
H
DPh
D
PhCH3CH
3
H
DPh12
3
4
12
3
‘R’
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CH3
H
DPh
D
PhCH3CH
3
H
DPh12
3
4
12
3
‘R’
View from bottom
H
CH3
DPh
D Ph
CH3
H
CH3
DPh1
2
3
4
1
2
3
‘S’
View from side
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Polarizer
Tube
Analyzer
Polarizer
Tube
Analyzer
Properties of enantiomers
Physical properties (bp, mp, solubility, pKa, pKb, thermal
stability, etc..) all identical
Rotate the plane of polarization of plane polarized light
optical activity
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Properties of enantiomers
Why do chiral molecules react differently with biological
molecules?
R S
A A A B
C B C A
A’ A’ A’ B’
C’ B’ C’ A’
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Different enantiomers behaviour
Absorption (membrane selectivity)
Metabolism
Binding to other reseptors than target (loss, side
effects)
Binding to target reseptor
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Importance of stereochemistry
Efficacy, adverse effects, and toxicity of drugs may be
enantiospecific
Example 1: Atorvastatin, fluvastatin, and rosuvastatin
(anti-hypercholesterolemia) exist in four optical forms, but they are currently used as enantiopure drugs, i.e.,
only one single enantiomer.
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CH3
HOH
HCH3NH
Ph
CH3
OHH
NHCH3
H
Ph
(-)-Ephedrine (+)-ephedrine (+)-pseudoephedrine (-)-pseudoephedrine
(vasoconstrictor)
36 11 7 1
(R)
(R)
(S)
(S)
I II
CH3
OHH
HCH3NH
Ph
CH3
HOH
NHCH3
H
Ph
(S)
(R)
(R)
(S)
III IV
CH2Ph
CH3
HMeNH
CH2Ph
CH3
NHMeH
I II
(R)(S)
Methamphetamine
10X more potent
CNS stimulant
Less cardiovascular
desoxyephedrine
Importance of stereochemistry
Example 2: Ephedrine
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O N
CH3
NH2
Ph
O N
CH3
NH2
Ph
Cis-4-methylaminorex
Potent amphetamine
psychostimulant
R S S S
NH
CH3
NCH3
H
Effective dose
(5.5 mg/Kg) (>150 mg/Kg)
H CH3
COOH
MeO
CH3
H
OMe
HOOC
S(+) R(-)
Naproxen
Importance of stereochemistry
Example 3:
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Channel blockers
Calcium channel blockers prevent calcium from entering
cells of the heart and blood vessel walls, resulting in
lower blood pressure.
Example 1: Diltiazem and verapamil are both chiral,
possessing asymmetric centers. In each case, the
dextro-rotatory (i.e. the (+)-enantiomer) is approximately
10 times more potent as a calcium channel blocker than
the levo-rotatory (i.e. (–)-enantiomer ).
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Example 2: Amlodipine is used therapeutically as a
racemic mixture, composed of S- and R-enantiomers,
but its calcium channel-blocking effect is confined to S-
amlodipine; R-amlodipine has 1000-fold less activity than
its S-enantiomer. The affinity of its levorotary (-)-
enantiomer to the calcium channels is 1,000 times
superior to that of its dextrorotary (+)-enantiomer.
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Receptors/enzymes
The biological receptors (including enzymes) for drugs are
chiral they respond to only one isomer of a ligand/drug.
The isomer with desired biological activity is called eutomer
and the other isomers are called distomer.
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Receptors/enzymes
There is an enzyme with three
binding site for an amino acid.
If the amino acid was in a non-
enzymatic reaction, the
stereochemistry is selected by bulky
groups’ positions and we will get all
the stereoisomers even though one
isomer will be preferred.
But in an enzymatic reaction, the
amino acid has to bind with the
specific binding site before catalysis.
Thus enzymatic reaction is always
stereoisomer specific.
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other isomers of the molecule may be catalysed by the
enzyme if the enzyme has additional binding site, but
even then the catalysis is usually weak.
the binding specificity of a chiral receptor site for a chiral
molecule is usually only favorable in one way The
biological receptors (including enzymes) for drugs are
chiral. Therefore they respond to only one isomer of a
ligand/drug.
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Anaesthesia
More than half of the synthetic agents used in anaesthesia practice are chiral drugs.
Almost all are administered as racemic mixture, rather
than as single pure enantiomers.
Examples:
- inhalational general anaesthetics (e.g. isoflurane),
- intravenous anaesthetics (e.g. etomidate, thiopentone),
- neuromuscular blocking agents (e.g. cisatracurium)
- local anaesthetics (e.g. ropivacaine and levobupivacaine)
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Etomidate
Administered as a single
isomer: R-isomer
Site of action: GABAA
receptor.
R-isomer is 15 times more
potent than the S-isomer.
S-isomer lacks hypnotic
activity.
etomidate
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Ketamin
S-ketamine is 2-4 times more
potent than R-ketamine as an
anaesthetic and analgesic agent.
R-ketamine: emerge reactions like
hallucinations, vivid dreams and
agitation
Metabolism of S-ketamine by liver
microsomes is 20% greater than R-
ketamine and 10% greater than the
racemate, faster clearance of the
drug.
ketamin
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Isoflurane
S(+)-isoflurane reported to be
50% more potent than R(-)-
isoflurane
Both enantiomers are equally
soluble in the lipid bilayers.
S-isoflurane induced about 50%
longer sleep times than R-
isoflurane
Majority of the inhalational
agents currently used are chiral
except, sevoflurane
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isoflurane
Other anaesthesia
other agents (e.g. levosimendan, dexmedetomidine,
L-cysteine).
levosimendan dexmedetomidine
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Adrenaline
The (-) enantiomers exert stronger effect i.e; heart
rate increases
X-ray crystallography of adrenaline Enantiomers shown
that negative form has R configuration and the positive
form has S configuration
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Neuromuscular blocking agents:
atracurium
Intermediate duration non-depolarizing neuromuscular
blocker.
Causes histamine release, transient hypotension,
tachycardia, facial or truncal flushing.
Contains 4 chiral centres and is a mixture of 10 optical and
geometric isomers.
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atracurium
Potential advantages of single
enantiomer products
Less complex, more selective pharmacodynamic
profile
Potential for an improved therapeutic index
Less complex pharmacokinetic profile
Reduced potential for complex drug interactions
Less complex relationship bebetween plasma
concentration and effect
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Absorption and stereoselectivity
For the majority of racemic drugs, absorption
appears to be by passive diffusion, provided no
stereoselectivity.
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Carrier mediated transporter
Stereo selective
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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methotrexate
Distribution
Stereo selective 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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Example:
R-propranolol binding to
albumin is greater than S-
propranolol and the opposite is
observed for 1–acid
glycoprotein (AAG)
R-propranolol: highly albumin
bound, less potent
S-propranolol: highly bound to
AAG, available as unbound,
40-100 time more potent
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propranolol
Terimakasih
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