Download m5zn_776561dda50e649

‫بسم هللا الرحمن الرحيم‬
‫"وسع ربنا كل ٍ‬
‫شئ علما‬
‫على هللا توكلنا ربنا افتح‬
‫بينناوبين قومنا بالحق‬
‫وأنت خير الف اتحين"‬
‫‪5/1/2017‬األعراف‬
‫اآلية ‪ 89‬من سورة‬
Continuous Assessment:
•
•
•
First Assessment Test
Second Assessment Test
Term Activity*
20%
20%
20%
Final Examination:
6.
Final Paper test Final Exam
5/1/2017
40%
2
Gareth Thomas. Medicinal , An Introduction, John Wiley and sons, Ltd, 1st
edition, 2000.
2. Williams, D.\a. and Lemeke, Foye’s Principle of Medicinal Chemistry ,
Lippincott Williams and Wilkins, Philadephia, PA., 5th edition, 2002.
3. Gareth Thomas Medicinal Chemistry, An Introduction, 2nd
Edition. Wiley-Interscience (2008)
4. Graham L. Patrick, An Introduction to Medicinal Chemistry, 3ed
Ed.; Oxford University Press (2005)
1.
5/1/2017
● Medicinal chemistry is a chemistry-based
discipline, also
involving aspects of
biological,
medical
and
pharmaceutical
sciences. It is concerned with the invention,
discovery,
design,
identification
and
preparation of biologically active compounds,
the study of their metabolism, the
interpretation of their mode of action at the
molecular level and the construction of
structure-activity relationships (SAR).
● Drugs are strictly defined as chemical
substances that are used to prevent or cure
5/1/2017
diseases
in human, animals and plants.
– The word drug, therefore, imposes an
action-effect context within which the
properties of a substance are described.
For example when a drug is defined as an
analgesic, it means that it is used to
treat pain ….. Thus a drug may described
as
having
analgesic,
vasodepressor,
anticonvulsant,
antibacterial,
…….…etc
properties.
5/1/2017
● Drugs activity, solubility in plasma and
distribution to various tissues is dependent
on their physicochemical properties. Even the
interaction of a drug with a receptor or an
enzyme is dependent on characteristics of a
drug molecule, such as ionization, electron
distribution, polarity and electronegativity.
To
understand
drug
action,
the
physicochemical parameters that make
this action possible should be also
understood.
●
5/1/2017
Drug names:
(nomenclature)
• Chemical
– 6-Chloro-3,4-dihydro-7-sulfamoyl-2H1,2,4-benzothiadiazine 1,1-dioxide
•
•
Trade
– Hydrodiuril®,
Hydroaquil®,
Esidrex®,
Urozide®, Novohydrazide® etc.
Many
others
Generic
– Hydrochlorothiazide
5/1/2017
Parenteral
Route
Target Receptor Site
(Desired Biological Activity)
Drug in
Solution
Drug in
Formulation
Drug in
Blood
Membrane
Deaggregation,
Dissolution
Absorption across
Membrane
Excretion
5/1/2017
Tissue Depots
Non-Target Receptor Site
(Side Effects)
Pharmaceutical Pharmacokinetic Pharmacodynamic
Phase
Phase
Phase
Dosage form
Tablet, etc.
5/1/2017
Absorption
Distribution
Metabolism
Excretion etc
Drug action
Drug-receptor
Interaction
Disposition of a drug after oral administration
5/1/2017
Disposition of a drug after oral administration
Tissue Reservoirs
Receptors
D + R  DR
Free drug
Plasma protein
binding
5/1/2017
Biotransformation
Liver D -> metabolite M
Excretion
Cell Structure
•
Human, animal and plant cells are eukaryotic cells
•
The nucleus contains the genetic blueprint for life
(DNA)
•
The fluid contents of the cell are known as the
cytoplasm
•
Structures within the cell are known as organelles
•
Mitochondria are the source of energy production
•
Ribosomes are the cell’s protein ‘factories’
•
Rough endoplasmic reticulum is the location for protein
synthesis
5/1/2017
Cell Membrane
Exterior
High [Na+]
Proteins
Phospholipid
Bilayer
Interior
High [K+]
5/1/2017
Cell Membrane
CH2CH2NMe3
Polar
Head
Group
Polar
Head
Group
O
O
P
O
O
CH2 CH
O
O
Hydrophobic Tails
Hydrophobic Tails
5/1/2017
CH2
O
O
Cell Membrane
CH2CH2NMe3
Polar
Head
Group
O
O
P
O
O
CH2 CH
O
O
Hydrophobic Tails
5/1/2017
CH2
O
O
Cell Membrane
•
The cell membrane is made up of a phospholipid
bilayer
•
The hydrophobic tails interact with each other by
van der Waals interactions and are hidden from the
aqueous media
•
The polar head groups interact with water at the
inner and outer surfaces of the membrane
•
The cell membrane provides a hydrophobic barrier
around the cell, preventing the passage of water and
polar molecules
•
Proteins are present, floating in the cell membrane
•
Some act as ion channels and carrier proteins
5/1/2017
Drug Targets - Cell Membrane Lipids
TUNNEL
HO2C
OH
OH CO2H
Sugar
Sugar
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
Polar tunnel formed
Escape route for ions
CELL
MEMBRANE
5/1/2017
Sugar
HO2C
Sugar
OH
OH
CO2H
Diagram of Cell Membrane
Lipid
exterior
Protein
Hydrophilic
region
Hydrophobic
interior
5/1/2017
Cross-section through the cell membrane
Membrane passage of drugs
5/1/2017
Mechanisms of Drug Absorption
1. Passive Diffusion
The transfer of most drugs across a biological membrane
occurs by passive diffusion, a natural tendency for molecules to
move from higher concentration to one of lower concentration.
This movement of drug molecules is caused by the kinetic
energy of the molecules. It is a major route for the transfer of
uncharged and non-polar solutes that readily dissolve in lipids
through membranes.
5/1/2017
PASSIVE DIFFUSION
= Solute molecule
Lipid membrane
Side A
Side B
1. Driving force is a concentration or electrochemical gradient
2. At equilibrium, [drug]Side A = [drug]Side B ; no further
net movement of drug
5/1/2017
2. FACILITATED or Carrier Mediated DIFFUSION
It is the transport of a drug through a membrane by the action of
transporter proteins. The drug combines with a specific proteins
causing this protein to change its confirmation which result in the
transport of the solute from one side of the membrane to the other.
• Some solutes diffuse across membranes down
electrochemical gradients more rapidly than expected from
size, charge, and partition coefficients
• “Ping-Pong” mechanism explains facilitated diffusion
• Carrier protein exists in two principal conformations:
– “Pong” state - exposed to high [solute], solutes bind to
specific sites on carrier protein
– Conformational change exposes carrier to lower [solute] “ping” state
5/1/2017
– Process is reversible, net flux depends on concentration
gradient
FACILITATED or Carrier Mediated DIFFUSION
Lipid membrane
Side A
Side B
C
C
C
C
C
= Solute molecule
C = carrier protein
1. Process involves a carrier protein, “C”
2. Driving force is a concentration
or electrochemical gradient
3. Limited number of carrier proteins in
membrane; i.e., a saturable process
4. At equilibrium, [drug]Side A = [drug]Side B;
no further net movement of drug
5. No expenditure of energy
•The requirement for carrier mediated transport is
structural similarities between the drug and the substrate
5/1/2017 transported by these carriers.
normally
3- ACTIVE TRANSPORT
= Solute molecule
Lipid membrane
Side B
Side A
CATP
PUMP
1. E required - process driven by ATPdependent pump
2. ATP-pump is used to drive a solute
against its concentration or electrochemical gradient
3. Limited number of pumps in membrane;
i.e., a saturable process
4. At equilibrium, [drug]Side A < [drug]Side B
ADP
5/1/2017
• Active transport
differs from passive
diffusion in the following ways:
1. The transport of the drug occurs against a
concentration gradient.
2. The transport mechanism can become
saturated at high drug concentration .
Facilitated diffusion
or active transport
Rate of
drug entry
into cells
Passive diffusion
5/1/2017
Drug concentration
3. A specificity for a certain molecular structure may
promote competition in the presence of a similarity
structured compound.
Examples of substances that are active
transported include amino acids, methyldopa,
5-FU, penicillamine and levodopa.
5/1/2017
Example: Levodopa for dopamine
HO
CH2
HO
CH2
HO
NH2
Dopamine
•
Useful in treating Parkinson’s Disease
•
Too polar to cross cell membranes
and BBB
5/1/2017
CH2
CO2H
C
HO
H
NH2
Levodopa
•
More polar but is an amino acid
•
Carried across cell membranes by
carrier proteins for amino acids
•
Decarboxylated in cell to dopamine
Cell
Cell
Membrane
Membrane
Cell
5/1/2017
RECEPTOR
Carrier
Protein
Cell
Cell
Membrane
Membrane
Cell
5/1/2017
RECEPTOR
Cell
Cell
Membrane
Membrane
Cell
5/1/2017
RECEPTOR
Cell
Cell
Membrane
Membrane
Cell
5/1/2017
RECEPTOR
Cell
Cell
Membrane
Membrane
Cell
5/1/2017
RECEPTOR
Cell
Cell
Membrane
Membrane
Cell
5/1/2017
RECEPTOR
Cell
Cell
Membrane
Membrane
Cell
5/1/2017
RECEPTOR
Cell
Cell
Membrane
Membrane
Cell
5/1/2017
RECEPTOR
Cell
Cell
Membrane
Membrane
Cell
5/1/2017
RECEPTOR
Cell
Cell
Membrane
Membrane
Cell
5/1/2017
RECEPTOR
Cell
Cell
Membrane
Membrane
Cell
5/1/2017
RECEPTOR
Cell
Cell
Membrane
Membrane
Cell
5/1/2017
RECEPTOR
Cell
Cell
Membrane
Membrane
Cell
5/1/2017
RECEPTOR
Cell
Cell
Membrane
Membrane
Cell
5/1/2017
RECEPTOR
Cell
Cell
Membrane
Membrane
Cell
5/1/2017
RECEPTOR
Cell
Membrane
Cell
5/1/2017
Cell
Membrane
Cell
5/1/2017
Cell
Membrane
Cell
5/1/2017
Cell
Membrane
Cell
5/1/2017
Blood
supply
H2N
Brain
cells
H2N
COOH
COOH
Enzyme
L-Dopa
H2N
BLOOD BRAIN
BARRIER
5/1/2017
Dopamine
4. Convective Absorption
The absorption of small molecules, with molecular
radii less than about 4Ǻ , through water filled
pores of biological membrane.
5. Ion-Pair Absorption
The absorption of a relatively large organic anion
through its combination with a relatively large
cation to form an ion pair which will cross a waterorganic solvent interface and transfer to an
organic phase.
5/1/2017
6- Endocytosis/Exocytosis
• For macromolecules or large complexes
endocytosis
exocytosis
5/1/2017
5/1/2017
The pH-Partition Hypothesis on Drug Absorption
– This theory provides a basic framework for
understanding of drug absorption from the GIT and
drug transport across the biological membrane. The
principle points of this theory are:
1. The GIT and other biological membranes act as lipid
barriers.
2. The un-ionized form of the acidic or basic drug is
preferentially absorbed.
3. Most drugs are absorbed by passive diffusion.
4. The rate of drug absorption and the amount of drug
absorbed are related to its oil-water partition
coefficient, the more lipophilic the drug, the faster
is its absorption.
5. Weak
acidic and neutral drugs may be absorbed
5/1/2017
from stomach but basic drugs are not.
IONIZATION (pKa)
Ionization and pH at Absorption site
 The fraction of the drug existing in its unionized form in a solution is a function of both the
dissociation constant and the pH of the solution at
the absorption site.
5/1/2017
IONIZATION of DRUGS
Drug Absorption & Transport Depends on:
Drug solubility
Partition coefficient
Ionization
Drug Transport is a Compromise Between:
Increased H2O solubility of ionized
Superior passage of unionized (undissociated)
5/1/2017
IONIZATION of DRUGS
IN GENERAL: drugs pass through membranes
in undissociated form but act as ions, if possible
pKa range of 6 – 8 seems
most
favorable
(for
passive transport)
5/1/2017
5/1/2017
CALCULATION OF IONIZATION
Ionizable drugs (weak acids & bases) do so,
depending upon:
• Dissociation constant (pKa)
• pH of the environment
5/1/2017
WEAKLY ACIDIC DRUGS
Ka
acid 1
5/1/2017
base 2
conjugate
acid 2
conjugate
base 1
Henderson-Hasselbalch
WEAKLY ACIDIC DRUGS
5/1/2017
WEAKLY BASIC DRUGS
Autoprotolysis Constant of Water (Kw)
Kw
5/1/2017
use this equation to
define the Kb term on
next slide
WEAKLY BASIC DRUGS
Kb
base 1
5/1/2017
acid 2
conjugate
acid 1
conjugate
base 2
WEAKLY ACIDIC DRUGS
% ionized =
100
1 + 10
pKa pH
(pKa
-
pH)
% ionized
5.4
6.4
7.4
8.4
7.4
7.4
7.4
7.4
100/1+10-2 = 100/1.01 = 99.01%
100/1+10-1 = 100/1.1 = 90.91%
50%
100/1+101 = 100/11 = 9.09%
9.4
7.4
100/1+102 = 100/101
5/1/2017
= 0.99%
WEAKLY BASIC DRUGS
% ionized =
100
1 + 10
(pH
- pKa)
pKa pH
5.4 7.4
% ionized
100/1+102 = 100/101 = 0.99%
6.4
7.4
8.4
7.4
7.4
7.4
100/1+101 = 100/11
9.4
7.4
100/1+10-2 = 100/1.01= 99.01%
5/1/2017
= 9.09%
50%
100/1+10-1 = 100/1.1 = 90.91%
IONIZATION SUMMARY
Remember
 For an acid drug, the smaller the pKa, the
stronger the acid
 For a basic drug, the larger the pKa (i.e. the
smaller the pKb), the stronger the base
5/1/2017
IONIZATION SUMMARY
A useful relationship
 Acid strength may be expressed as Ka or Kb of
its conjugate base.
 Ka of an acid may be calculated if Kb is known.
 Stronger the acid, the weaker its conjugate
base.
5/1/2017
knowing pKa and pH allows
determination of % ionization
5/1/2017
Acidic groups
100% ionized when pH
is  2 units above pKa
Basic groups
100% ionized when pH
is  2 units below pKa
Acidic drugs that are
highly ionized at pH 7.4
H
S
Drug
H
N
N
O
O
O
OH
HO
O
O
NH
O
S
O
NH2
5/1/2017
Penicillin G
2.76
ASA
3.49
Sulfisoxazole
5.00
O
O
N
pKa
All > 99%
ionized
Basic drugs that are highly
ionized at pH 7.4
N
O
O
OH
Drug
pKa
Atropine
9.65
Procaine
8.80
Chlorcyclizine
8.15
O
N
O
NH2
N
Cl
5/1/2017
N
All > 85%
ionized
Groups on receptors may also be
highly ionized at pH 7.4
O
Acidic groups
pKa
aspartic acid
3.7
glutamic acid
4.30
phosphoryl
1.00
OH
HO
NH2
O
NH2
HO
OH
O
O
O
HO
P•
OH
5/1/2017
All > 99%
ionized
Groups on receptors may also be
highly ionized at pH 7.4
Basic groups
NH2
H
N
H2N
NH
H2N
pKa
OH
arginine
12.5
O
lysine
10.5
glutamine
9.10
O
H2N
OH
NH2
H2N
OH
O
O
All > 98%
ionized
5/1/2017
IONIZATION Examples
What does this pKa refer to?
propranolol
i.e. is there an acidic
functional group?
pKa = 9.45
Is drug acidic, basic, amphoteric?
Kb
base 1
What is the pKb?
5/1/2017
conjugate
acid 1
acid 2
4.55
conjugate
base 2
IONIZATION Examples
sulfasalazine
What do the pKa’s refer to?
i.e. are there acidic and/or
basic functional groups?
pKa = 2.4, 9.7, 11.8
Ka
acid 1
5/1/2017
base 2
conjugate
acid 2
conjugate
base 1
IONIZATION of POLYPROTIC DRUGS
Polyprotic acids donate >1 proton
Each dissociation stage has an equilibrium
expression and therefore pKa.
pKa1 7.4
pKa2 ~ 12 - 13
phenobarbital
5/1/2017
It becomes
progressively
more difficult
to donate
protons
5/1/2017
5/1/2017
 Methamphetamine, with a pKa
dissolved in a solution at pH 7.87:
5/1/2017
of
9.87,
is
 diethylbarbituric has an unionized H:B form, and an
ionized B: form. It has a pKa of 8.0, and is dissolved in fluid
with a pH of 7:
5/1/2017
Change of the ionization state will affect:
i. Movement from aqueous phase to lipid upon
crossing a membrane
ii. Movement from aqueous phase to hydrophobic
binding pocket
iii. Movement from aqueous phase to location
adjacent to a charged or polar residue in an
active site
– In order to elicit a pharmacological effect, drugs
must be sufficiently soluble in water to be
absorbed and distributed throughout the body.
They must also have sufficient lipophilicity to be
able to pass through biological membranes.
5/1/2017
Water Solubility and Hydrogen Bonding
– A stronger and important form of chemical bonding is the
dipole-dipole bond, specific example of which is the hydrogen
bond.
– A dipole results from the unequal sharing of a pair of electrons
making up a covalent bond. This occurs when the two atoms making
up the covalent bond differ significantly in electronegativity.

N

.............. H

H
H
O
O

............ H
S
R
H
Hydrogen Bond
Hydrogen bonding of an amine to water and a thiol to water
– Water has a dipole moment, due to the 104.5 degree
bond angle, and the pull of electronegative oxygen on
the attached hydrogens. This induced polarity gives
water a higher boiling point and melting point than other
hydrides (e.g. H-S-H, hydrogen sulfide, is a gas at
room temperature). This dipole also allows water to
hydrogen bond, and in pure water, it H-bonds to itself,
forming a lattice.
5/1/2017
– Ionized molecules carry charge and favor interaction with
water dipoles making these molecules water-soluble. Other
molecules, e.g., glucose, are not charged, but, have an uneven
electron density and are thus polar molecules that interact
with water dipoles and are freely soluble in water.
– This association with water molecules makes these watersoluble compounds less soluble in oils, fat, and lipid. These
types of molecules are said to be hydrophilic (water-liking).
– In contrast, nonpolar and noncharged molecules tend to
be much more lipid-soluble or hydrophobic (water-hating)
or lipophilic (lipid-liking).
5/1/2017
Partition Coefficient (Lipid/Water Partition Coefficient)
 It is a means of expressing a drug's solubility is lipid
versus water. A drug is added to a two-phase solution of oil
(or other organic solvent like 1-octanol) and water, mixed,
and the concentration of drug in the organic and water
phases determined. The ratio of the two phases reflects
the relative lipid/water solubility.
How does one determine a drug’s partition coefficient?
1. Add drug
2. Equilibrate
3. Determine [Drug]org and [Drug]aqu
Organic
phase
5/1/2017
Aqueous
phase
4. Calculate Korg/aqu
Mathematically,
Korg/aqu =
[Drug]org
[Drug]aqu
Lipid-Water Partition Coefficient
– The ratio of the concentration of the
drug in two immiscible phases: a
nonpolar liquid or organic solvent
(representing the membrane); and an
aqueous buffer, pH 7.4 (representing
the plasma)
5/1/2017
Lipid-Water Partition Coefficient
• The higher the lipid/water p.c. the greater
the rate of transfer across the membrane
–
polarity of a drug, by increasing
ionization will
the lipid/ water p.c.
–
polarity of a drug, suppression of
ionization will
the lipid/ water p.c.
5/1/2017
Lipid-Water Partition Coefficient
• The higher the lipid/water p.c. the greater
the rate of transfer across the membrane
–
polarity of a drug, by increasing
ionization will
the lipid/ water p.c.
–
polarity of a drug, suppression of
ionization will
the lipid/ water p.c.
5/1/2017
A drug’s partition coefficient, Korg/aqu is an index of the drug’s
lipophilicity.
Log P = 1 means 10:1 Organic:Aqueous
Log P = 0 means 1:1 Organic:Aqueous
Log P = -1 means 1:10 Organic:Aqueous
In general, assuming passive absorption
Optimum CNS penetration around Log P = 2 +/- 0.7
Optimum Oral absorption around Log P = 1.8
Optimum Intestinal absorption Log P =1.35
Optimum Colonic absorption Log P = 1.32
Optimum Sub lingual absorption Log P = 5.5
5/1/2017
Optimum Percutaneous Log P = 2.6 (& low mw)
– The partition ratio of a given drug will determine
its solubility in plasma, its ability to traverse cell
membranes, and which tissues it will reach.
– Drugs must have some aqueous solubility since this
is essential for absorption through membranes, and
for the production of an adequate concentration at
the site-of-action. A balance between hydrophilicity
and lipohilicity is necessary. This must be taken
into account when chemically modifying a drug for
optimal activity.
5/1/2017
The relationship between physicochemical
properties and drug action
“Theoretical representations”
 Overton-Meyer Hypothesis
o The hypothesis states that, the higher the
partition ratio P, the higher the pharmacological
effect.
 The Ferguson Principle
o The concentration of a drug in plasma is directly
proportional to its activity.
o Ferguson Constant is represented by
5/1/2017
where:
X
– High thermodynamic activity means that the
activity of the drug is based on its physicochemical
properties only, such as in a gaseous anesthetic. Such
5/1/2017 are known as non-specific agents.
drugs
– Low thermodynamic activity means that the
activity of the drug is based on its structure
rather than physicochemical properties.
– Agents in this category are called specific
agents, and their activity at low concentrations
infers that they have a specific receptor.
5/1/2017
Electronic Effects
Hammett Substituent Constant (s)
•
•
The constant (s) a measure of the e-withdrawing or edonating influence of substituents
It can be measured experimentally and tabulated
(e.g. s for aromatic substituents is measured by comparing the
dissociation constants of substituted benzoic acids with benzoic
acid)
X
X
CO2H
X=H
5/1/2017
CO2
+
K H = Dissociation constant= [PhCO2 ]
[PhCO2H]
H
Hammett Substituent Constant (s)
X= electron withdrawing group (e.g. NO2)
X = electron
withdrawing
group
X
X
CO2H
CO2
+
H
Charge is stabilized by X
Equilibrium shifts to right
KX > K H
s
X
= log
KX
= logKX - logKH
KH
Positive value
5/1/2017
Hammett Substituent Constant (s)
X= electron donating group (e.g. CH3)
X =donating
electron
X = electron
withdrawing
group group
X
X
CO2H
CO2
+
H
Charge destabilized
Equilibrium shifts to left
KX < K H
s
X
= log
KX
= logKX - logKH
KH
Negative value
5/1/2017
Hammett Substituent Coefficient
5/1/2017
5/1/2017
s value depends on inductive and resonance effects
s value depends on whether the substituent is meta or para
ortho values are invalid due to steric factors
5/1/2017
 Linear free energy relationship
5/1/2017
ρ the slope of the line, is a proportionality
constant pertaining to a given equilibrium.
σ is a descriptor of the substituents (Hammett constant ).
– The magnitude of σ gives the relative strength of
the electron-withdrawing or -donating properties
of the substituents.
• σ is positive if the substituent is electronwithdrawing
and negative if it is electron-donating.
5/1/2017
Some illustrative values of ρ
Some illustrative values of σ
5/1/2017
Applications of the Hammett Equation
1. Prediction of the pKa of ionization equilibria.
For benzoic acid derivatives:
5/1/2017
Given σmeta = 0.71 for nitro groups and σpara = - 0.13
for methyl groups, the calculated pKa=2.91, which
compares favorably with the experimental value of
2.97.
5/1/2017
2. Selection of the substituents for optimum
biological
activity.
e.g. QSAR relating the inhibition of bacterial
growth by a series of sulfonamides
A QSAR was developed based on the σ values of the
substituents
where C is the minimum concentration of compound
that inhibited growth of E. coli.
It was found that electron-withdrawing substituents
5/1/2017
favor
inhibition of growth.
Hansch Constant (p)
 Hansch
derived
constants
for
the
contributions of substituents to the partition
coefficient. The lipophilicity constant, π, is
defined as:
π = log Px - log PH = log (Px/PH)
where Px is partition constant for the compound
with X as substituent and PH is the partition
constant for the parent.
Tables of values of π for other substituents are available.
5/1/2017
p values for various substituents on
aromatic rings
CH3 t-Bu
OH CONH2 CF3
0.52 1.68 -0.67
-1.49
Cl
F
1.16 0.71 0.86 0.14
Theoretical Log P for chlorobenzene
= log P for benzene + p for Cl
= 2.13 + 0.71 = 2.84
5/1/2017
Br
p values for various substituents on
aromatic rings
CH3 t-Bu OH
CONH2 CF3 Cl
0.52 1.68 -0.67 -1.49
Br
1.16 0.71 0.86 0.14
Theoretical Log P for meta-chlorobenzamide
= log P for benzene + p for Cl + p for CONH2
= 2.13 + 0.71 - 1.49 = 1.35
5/1/2017
F
The following are the p values for various substituents on an
aromatic ring:
-CF3 (1.07), -Br (0.94), -OCH3 (-0.02), -CH2OH (-1.03). Which
functional group listed above will increase the water solubility of
the following drug the most (ie. we replace the R- group with one of
the substituents).
A) -CF3 (1.07)
B) -Br (0.94)
C) -OCH3 (-0.02)
D) -CH2OH (-1.03)
E) They will all make the drug equally lipophilic
5/1/2017
Steric Effects
 The third major factor that often must be
considered in QSAR involves steric effects.
 For studies involving reactivity of organic
compounds, a steric parameter, Es, was
defined by Taft as :
where k is the rate constant for the acid
hydrolysis of esters of the type
5/1/2017
– Assuming
the
electronic
effects
of
substituent X can be ignored, the size of X will
affect the transition state and hence the rate
of reaction.
– By definition Es = 0 for X=H.
– Tables of values of Es for other substituents
are available.
5/1/2017
Steric Effects

much harder to quantitate
 Examples are:
Taft’s steric factor (Es)
(~1956),
experimental value based on rate constants

an
 Molar refractivity (MR)--measure of the volume
occupied by an atom or group--equation includes
the MW, density, and the index of refraction—
 Verloop steric parameter--computer program
uses bond angles, van der Waals radii, bond
lengths
5/1/2017
Hansch Approach
A drug's activity was really a function of
two processes:
1. its transportation from point of entry to
receptor site(s) (pharmacokinetics).
2. its
interaction
with
the
receptor
(pharmacodynamics).

– Hansch proposed that the ability of a drug to
get through a membrane might be modeled by
its partition coefficient between a lipid-type
solvent and water
5/1/2017
The suggested model for a drug traveling
through the body to its receptor site might be:
log 1/C = -k(log P)2 + k'(log P) + k"
where potency is expressed as log (1/C) and C is
the concentration of a drug that provides some
standard biological effect.
 This equation has the format for a parabola
 The significance of this observation is that an
optimum hydrophobicity may exist.
5/1/2017
Log (1/C)
o
Log P
Log P
Optimum value of log P for anaesthetic activity = log Po
5/1/2017
– Accordingly several membranes may have to
be traversed for compounds to get to the
target site, and compounds with the greatest
hydrophobicity will become localized in the
membranes they encounter initially, thereby
slowing their transit to the target site.
– Hansch proposed also that there should be a
linear free energy relationship (like the
Hammett equation) between lipophilicity and drug
activity and that this might be indicated by the
partition coefficient
5/1/2017
Hansch Linear Free Energy Model
 Hansch has derived a general equation based
on linear free-energy considerations.
 In this equation is the ability to incorporate
parameters which encompass the full range of
known biological requirements for drug activity.
 Among theses terms for biological transport,
drug/enzyme binding energies and substituent
effects (both electronic and steric).
 The most general form of Hansch equation is:
5/1/2017
log 1/C = -aπ2 + bπ + ρσ + c
Log 1/C = k1P - k2P2 + k3s + k4Es + k5
Where
activity expressed as 1/C, C = concentration,
π is the Hansch constant (measure of lipophilicty),
ρ is constant related to the given molecule,
σ is the Hammett substituent constant which is a
measure of the electronic effect.
Es Taft’s constant
5/1/2017
Hansch Analysis
• Look at size and sign for each
component of the equation.
• Values of r <<0.9 indicate equation not
reliable
• Accuracy depends on using enough
analogs, accuracy of data, & choice of
parameters.
5/1/2017
Examples for Hansch equations
log 1/C = 1.22 p – 1.59 s + 7.89
(n = 22; r = 0.918)
log 1/C = 0.398 p + 1.089 s + 1.03 Es + 4.541
(n = 9; r = 0.955)
5/1/2017
Examples:
Adrenergic blocking activity of b-halo-b-arylamines
Y
X
CH CH2
1 

Log C =
NRR'
1.22 p - 1.59 s + 7.89
Conclusions:
• Activity increases if p is + (i.e. hydrophobic substituents)
• Activity increases if s is negative (i.e. e-donating substituents)
5/1/2017
For the antibacterial activity of substituted phenols
OH
X
log 1/C = 0.684 log P – 0.921σ + 0.268
5/1/2017
For a series of phosphonate esters, cholinesterase inhibitors
O
O P OCH2CH3
R
O2N
log K = -0.152 π – 1.68 σ + 4.053 Es + 7.212
Where
K is the inhibition constant,
σ is the Hammett substituent constant for
aliphatic systems
Es is the Taft steric constant.
In this example steric effect of the substituents plays an
important
role. The bulkier groups cause a decrease in
5/1/2017
cholinesterase inhibition.
一For the antibacterial effects on gram-negative bacteria of a series of
diguanidines:
NH
(CH2)n
(NH-C-NH2)2
log 1/C = -0.081 π2 + 1.483 π – 1.578
5/1/2017
Example: Antimalarial activity of phenanthrene aminocarbinols
CH2NHR'R"
(HO)HC
X
Y
1
Log C = -0.015 (logP)2 + 0.14 logP + 0.27 SpX + 0.40 SpY + 0.65 SsX + 0.88 SsY + 2.34
Conclusions:
• Activity increases slightly as log P (hydrophobicity) increases
(note that the constant is only 0.14)
• Parabolic equation implies an optimum log Po value for activity
• Activity increases for hydrophobic substituents (esp. ring Y)
• Activity increases for e-withdrawing substituents (esp. ring Y)
5/1/2017
Electronic effect
Lipophilicityt
Steric effect
3-D space formed by lipophilic, electronic and steric coordinates
5/1/2017
Quantitative Structure-Activity Relationships
(QSAR):
QSARs are mathematical relationships linking
chemical structure and pharmacological activity
in a quantitative manner for a series of
compounds. Methods which can be used in QSAR
include
various
regression
and
pattern
recognition techniques.
5/1/2017
Quantitative Structure-Activity Relationship (QSAR) Models
Set of Compounds
Activity Data (Y)

Molecular Descriptors (Xi)
QSAR
Y = f(Xi)
Prediction
5/1/2017
Interpretation
Report On:
Stereochemistry of Drug Receptor Interaction
• Drugs
• Receptors
• Drug receptors interactions
• Effects of Stereochemistry of the drugs molecules on
their action.
)‫ درجات‬5( ‫ هـ‬6/6/1430 ‫أخر موعد لتقديم البحث‬
5/1/2017
‫اإلختبارالفصلى‬
‫سينعقد بحول هللا تعالى يوم‬
‫األحد ‪7‬جمادى األخر‪1430‬هـ املوافق‬
‫‪31‬مارس‪ 2009‬م الساعة السابعة صباحا‬
‫بقاعة املطالعة ‪2 215‬أ‬
‫‪5/1/2017‬‬
Free-Wilson Analysis
log (1/C) = S aixi + m
xi: presence of group i (0 or 1)
ai: activity group contribution of group i
m: activity value of unsubstituted compound
5/1/2017
Free-Wilson Approach
Advantages
• No need for physicochemical constants or tables
• Useful for structures with unusual substituents
• Useful for quantifying the biological effects of molecular
features that cannot be quantified or tabulated by the
Hansch method
Disadvantages
• A large number of analogues need to be synthesised to
represent each different substituent and each different
position of a substituent
• It is difficult to rationalise why specific substituents are good
or bad for activity
• The effects of different substituents may not be additive
(e.g. intramolecular interactions)
5/1/2017
Choosing suitable substituents
Substituents must be chosen to satisfy the following criteria:
•
•
•
A range of values for each physicochemical property studied
values must not be correlated for different properties (i.e. they
must be orthogonal in value)
at least 5 structures are required for each parameter studied
Substituent H
Me Et n-Pr
p
0.00 0.56 1.02 1.50
MR
0.10 0.56 1.03 1.55
Substituent H
Me OMe
p
0.00 0.56 -0.02
MR
0.10 0.56 0.79
5/1/2017
n-Bu
2.13
1.96
Correlated values.
Are any differences
due to p or MR?
NHCONH2 I
CN
-1.30
1.12 -0.57
1.37
1.39 0.63
No correlation in values
Valid for analysing effects
of p and MR.
 Craig Plot
Craig plot shows values for 2 different physicochemical
properties for various substituents
Example:
.
.
. . . ..
. .
.
.
. ..
.
.
.
.
.
.
.
.
.
+
1.0
+s -p
CF3SO 2
.75
CN
CH3SO2
SO 2NH2
NO2
.50
OCF3
.25
CO2H
-2.0
-p
-1.6
-1.2
-.8
-.4
F
.4
I
Br
Cl
.8
1.2
1.6
CH3CONH
-.25
OH
Me
2.0
+p
Et
t-Butyl
OCH3
-.50
NMe 2
NH2
-.75
-s -p
5/1/2017
SF5
CF3
CH3CO
CONH2
+s +p
-1.0
-
-s +p
• Craig Plot
•
Allows an easy identification of suitable substituents
for a QSAR analysis which includes both relevant
properties
•
Choose a substituent from each quadrant to ensure
orthogonality
•
Choose substituents with a range of values for each
property
5/1/2017
• Topliss Scheme
Used to decide which substituents to use if optimising
compounds one by one (where synthesis is complex and
slow)
Example: Aromatic substituents
H
4-Cl
L
4-OMe
L
M
E
E
4-CH3
L
M
E
M
3,4-Cl2
L
E
4-But
3-Cl
3-Cl
L
E
M
3-CF3-4-Cl
4-CF3
2,4-Cl2
3-NMe2
See Central
Branch
2-Cl
4-NMe2
L
E
M
3-Me-4-NMe2
4-NH2
5/1/2017
3-CH3
4-NO2
4-F
3-CF3
4-NO2
3,5-Cl2
3-NO2
M
3-CF3-4-NO2
• Topliss Scheme
Rationale
Replace H with
para-Cl (+p and +s)
Act.
+p and/or +s
advantageous
add second Cl to
increase p and s
further
Little
change
favourable p
unfavourable s
replace with Me
(+p and -s)
Act.
+p and/or +s
disadvantageous
replace with OMe
(-p and -s)
Further changes suggested based on arguments of p, s
and steric strain
5/1/2017
• Topliss Scheme
Aliphatic substituents
CH3
L
E
H; CH2OCH3 ; CH2SO2CH3
i-Pr
M
Et
L
E
L
M
Cyclopentyl
E
END
CHCl2 ; CF3 ; CH2CF3 ; CH2SCH3
Ph ; CH2Ph
5/1/2017
M
Cyclohexyl
Cyclobutyl; cyclopropyl
t-Bu
CH2Ph
CH2CH2Ph
• Topliss Scheme
Example
Order of
Synthesis
SO2NH2
R
1
2
3
4
5
R
H
4-Cl
3,4-Cl2
4-Br
4-NO2
Biological
Activity
High
Potency
M
L
E
M
M= More Activity
L= Less Activity
E = Equal Activity
5/1/2017
*
• Topliss Scheme
Example
R
N
N
N
N
Order of
Synthesis
CH2CH2CO2H
1
2
3
4
5
6
7
8
R
H
4-Cl
4-MeO
3-Cl
3-CF 3
3-Br
3-I
3,5-Cl 2
Biological
Activity
High
Potency
L
L
M
L
M
L
M
M= More Activity
L= Less Activity
E = Equal Activity
5/1/2017
*
*
*
Drug targets
Proteins
Lipids
Receptors
Enzymes
Carrier proteins
Structural proteins (tubulin)
Cell membrane lipids
Nucleic acids
DNA
RNA
Carbohydrates
Cell surface carbohydrates
Antigens and recognition molecules
5/1/2017
Drug targets
•
Drug targets are large molecules - macromolecules
•
Drugs are generally much smaller than their targets
•
Drugs interact with their targets by binding to binding
sites
•
Binding sites are typically hydrophobic pockets on the
surface of macromolecules
•
Binding
bonds
•
Most drugs are in equilibrium between being bound and
unbound to their target
•
Functional groups on the drug are involved in binding
interactions and are called binding groups
•
Specific regions within the binding site that are
involved
in binding interactions are called binding
5/1/2017
regions
interactions
typically
involve
intermolecular
Drug targets
Binding
regions
Drug
Binding
groups
Intermolecular
bonds
Binding site
Binding
site
Drug
Drug
Macromolecular target
Unbound drug
5/1/2017
Macromolecular target
Bound drug
Drug Receptor
• A macromolecular component of a cell with which a drug
interacts to produce a response (Usually a protein).
•
Globular proteins acting as a cell’s ‘letter boxes’
•
Located mostly in the cell membrane
•
Receive messages from chemical messengers coming from
other cells
•
Transmit a message into the cell leading to a cellular
effect
•
Different receptors
messengers
•
specific
for
different
chemical
Each cell has a range of receptors in the cell membrane
making it responsive to different chemical messengers
5/1/2017
Types of Protein Receptors
1.
2.
3.
4.
Regulatory – change the activity of cellular enzymes
Enzymes – may be inhibited or activated
Transport – e.g. Na+ /K+ ATP’ase
Structural – these form cell parts
5/1/2017
Structure and function of receptors
Nerve
Nerve
Signal
Messenger
Receptor
Response
Nucleus
5/1/2017
Cell
Cell
Chemical Messengers
Neurotransmitters: Chemicals released from nerve endings
which travel across a nerve synapse to bind with
receptors on target cells, such as muscle cells or another
nerve. Usually short lived and responsible for messages
between individual cells
Hormones: Chemicals released from cells or glands and
which travel some distance to bind with receptors on
target cells throughout the body
•
Chemical messengers ‘switch
undergoing a reaction
5/1/2017
on’
receptors
without
Structure and function of receptors
Nerve 1
Blood
supply
Nerve 2
Hormone
Neurotransmitters
5/1/2017
Mechanism
Induced fit
Messenger
Messenger
Messenger
Cell
Membrane
Receptor
Receptor
Cell
Cell
Receptor
Cell
message
Message
5/1/2017
Mechanism
•
Receptors contain a binding site (hollow or cleft in the
receptor surface) that is recognised by the chemical
messenger
•
Binding of the messenger involves intermolecular bonds
•
Binding results in an induced fit of the receptor protein
•
Change in receptor shape results in a ‘domino’ effect
•
Domino effect is known as Signal Transduction, leading
to a chemical signal being received inside the cell
•
Chemical messenger does not enter the cell. It departs
the receptor unchanged and is not permanently bound
5/1/2017
 The binding site
•
A hydrophobic hollow or cleft on the receptor surface
- equivalent to the active site of an enzyme
•
Accepts and binds a chemical messenger
•
Contains amino acids which bind the messenger
•
No reaction or catalysis takes place
Binding site
Binding site
ENZYME
5/1/2017
 Messenger binding
Messenger
M
Induced fit
•
Binding site is nearly the correct shape for the
messenger
•
Binding alters the shape of the receptor (induced fit)
•
Altered receptor shape leads to further effects signal transduction
5/1/2017
Bonding Forces
vdw
interaction
H-bond
Binding site
O
Ser
H
ionic
bond
CO2
Asp
Receptor
5/1/2017
Phe
•
Induced fit - Binding site alters shape to maximise
intermolecular bonding
Phe
Phe
O
O
H
Ser
CO2
Asp
Intermolecular bonds not
optimum length for
maximum binding strength
5/1/2017
Induced
Fit
Ser
H
CO2
Asp
Intermolecular bond
lengths optimised
Drug-Receptor Bonding
Ionic : the strongest type of non-covalent bond.
This results from the attraction of ions with
opposite charges
5/1/2017
R1
H
N
R
R2
O
R3
5/1/2017
Ion-Dipole : results when there is an attraction
between an ion and the partial charge of a dipole
of the opposite polarity
5/1/2017
Dipole-Dipole : Here a partially positive atom in a
dipole is attracted to a partially negative atom in
another dipole.
Hydrogen Bonding : A dipole-dipole interaction
where on of the constituents is a hydrogen
5/1/2017
attached to a heteroatom.
Hydrogen bonds
–
–
–
–
–
–
Vary in strength
Weaker than electrostatic interactions but stronger
than van der Waals interactions
A hydrogen bond takes place between an electron
deficient hydrogen and an electron rich heteroatom
(N or O)
The electron deficient hydrogen is usually attached
to a heteroatom (O or N)
The electron deficient hydrogen is called a hydrogen
bond donor (HBD)
The electron rich heteroatom is called a hydrogen
bond acceptor (HBA)
5/1/2017
- +
X H
Drug
Y Target
HBD
HBA
Drug Y
HBA
+ H X
Target
HBD
Hydrogen bonds
–
The interaction involves orbitals and is directional
–
Optimum orientation is where the X-H bond points
directly to the lone pair on Y such that the angle
between X, H and Y is 180o
X
Hybridised 1s
orbital
orbital
HBD
5/1/2017
Y
H
Hybridised
orbital
HBA
X
H
Y
Hydrogen bonds
•
Examples of strong hydrogen bond acceptors
- carboxylate ion, phosphate ion, tertiary amine
•
Examples of moderate hydrogen bond acceptors
- carboxylic acid, amide oxygen, ketone, ester,
ether, alcohol
•
Examples of poor hydrogen bond acceptors
- sulfur, fluorine, chlorine, aromatic ring, amide
nitrogen, aromatic amine
•
Example of good hydrogen bond donors
- Quaternary ammonium ion
5/1/2017
5/1/2017
Water can act as an H-bond Donor or Acceptor
Donates H
Accepts H
Lone pair electrons
5/1/2017
Examples of
H-bonding
interactions
5/1/2017
5/1/2017
The Hydrophobic Effect : when two alkyl chains
approach one another, water is extruded from the
space in between them, resulting in an increase in
entropy, and thus a decrease in energy.
5/1/2017
Charge-Transfer Complexes : a lone pair of
electrons is "shared" with a neighboring group that
has considerable π character.
5/1/2017
Van der Waals Forces : one carbon in a chain
approaches another carbon on a neighboring chain,
causing a perturbation known as an induced dipole.
These opposite partial charges then attract one
another.
5/1/2017
 Drugs may also bind to receptors using covalent
bonding. This may be a permanent bond, in which
case the receptor or enzyme target is "killed", or
it may be transient.
5/1/2017
Drug Interaction with Receptor
Lock & Key Model
– NT binds to receptor
NT = key
Receptor = lock
NT
Receptor A
5/1/2017
NT
Receptor A
5/1/2017
NT
Receptor A
5/1/2017
Receptor B
NT
Drug A
Receptor A
5/1/2017
Drug B
Receptor B
HO
HO
Activates and b
adrenoceptors
ADRENALINE =
CH
CH2
N
H
CH3
OH
PHENYLEPHRINE =
HO
*
CH
CH2
N
H
CH3
Activates 
adrenoceptors
OH
ISOPRENALINE =
HO
HO
CH
OH
5/1/2017
CH2
N
H
CH(CH3)2
*
Activates b
receptors
-Adrenoceptor
H-Bonding
region
H-Bonding
region
H-Bonding
region
5/1/2017
Van der Waals
bonding region
Ionic
bonding
region
-Adrenoceptor
ADRENALINE
5/1/2017
b-Adrenoceptor
ADRENALINE
5/1/2017
b-Adrenoceptor
SALBUTAMOL
5/1/2017
-Adrenoceptor
SALBUTAMOL
5/1/2017
-Adrenoceptor
SALBUTAMOL
5/1/2017
Dose Response Relationships
Dose = amount of drug administered to the patient
Response = effect in the body produced by the
drug
Drug + Receptor  Drug-Receptor Complex

Response
5/1/2017
100
3
Response 50
0
4
2
1
ED50
Log Drug Concentration [Molar]
KEY PARAMETERS
1. Dose required to produce any effect at all.
2. ED50 = effective dose to produce 50% response
3. Dose required to produce maximum effect
5/1/2017
4.
Dose that produces a toxic response.
Efficacy (or Intrinsic Activity) – ability of
a bound drug to change the receptor in a
way that produces an effect; some drugs
possess affinity but NOT efficacy
5/1/2017
Potency vs Efficacy
• Potency – how much drug is required to produce a certain
effect.
100
Response 50
0
2
1
ED50
Log Drug Concentration [Molar]
5/1/2017
Relative Potency
hydromorphone
morphine
codeine
Analgesia
aspirin
5/1/2017
Dose
Potency vs Efficacy
• Efficacy – how large an effect the drug produces.
100
Response
50
0
2
1
ED50
Log Drug Concentration [Molar]
5/1/2017
 Agonists Drugs
Drugs that interact with and activate receptors, they
possess both affinity and efficacy.
•
•
•
•
•
Agonist binds reversibly to the binding site
Similar intermolecular bonds formed as to natural messenger
Induced fit alters the shape of the receptor in the same way
as the normal messenger
Receptor is activated
Agonists are often similar in structure to the natural
messenger
Agonist
Agonist
Agonist
Induced fit
RE
5/1/2017
R
RE
Signal transduction
5/1/2017
 Antagonists Drugs
• Drugs that interact with receptors but do not
change them.
•They have affinity but no efficacy.
• Two types:
• Competitive (reversible) antagonists
• Non competitive (irreversible) antagonists
5/1/2017
• Competitive (reversible) antagonists
M
An
An
RE
•
•
•
•
•
•
•
R
Antagonist binds reversibly to the binding site
Intermolecular bonds involved in binding
Different induced fit means receptor is not activated
No reaction takes place on antagonist
Level of antagonism depends on strength of antagonist
binding and concentration
Messenger is blocked from the binding site
Increasing the messenger concentration reverses
antagonism
5/1/2017
5/1/2017
 Non competitive (irreversible) antagonists
X
Covalent Bond
X
OH
OH
O
Irreversible antagonism
•
•
•
•
•
Antagonist binds irreversibly to the binding site
Different induced fit means that the receptor is not
activated
Covalent bond is formed between the drug and the receptor
Messenger is blocked from the binding site
Increasing messenger concentration does not reverse
antagonism
5/1/2017
 Non competitive (reversible) allosteric antagonists
Binding site
unrecognisable
Binding site
ACTIVE SITE
(open)
Receptor
ENZYME
Allosteric
site
Induced
fit
(open)
Receptor
ENZYME
Antagonist
•
•
•
•
•
Antagonist binds reversibly to an allosteric site
Intermolecular bonds formed between antagonist and
binding site
Induced fit alters the shape of the receptor
Binding site is distorted and is not recognised by the
messenger
Increasing
messenger concentration does not reverse
5/1/2017
antagonism
Effectiveness, toxicity, lethality
• ED50 - Median Effective Dose 50; the dose
at which 50 percent of the population or
sample manifests a given effect; used with
quantal dr curves
• TD50 - Median Toxic Dose 50 - dose at
which 50 percent of the population
manifests a given toxic effect
• LD50 - Median Toxic Dose 50 - dose which
kills 50 percent of the subjects
5/1/2017
Quantification of drug safety
Therapeutic Index =
5/1/2017
TD50 or LD50
ED50
Drug A
100
sleep
death
Percent
50
Responding
0
ED50
5/1/2017
LD50
dose
Drug B
100
Percent
Responding
sleep
death
50
0
ED50
5/1/2017
dose
LD50
Stereochemical Aspects in
Drug Receptor Interaction
– Drug molecules must generally interact with
biomolecules in a very specific way to elicit a
pharmacological response.
– Biomolecules are chiral, they often discriminate
between isomers of a given drug molecule.
– The stereochemistry of a drug can impact its
ability to bind to its target.
5/1/2017
 The reason for chiral recognition by drug
receptors is a three-point interaction of the
agonist or substrate with the receptor or enzyme
active site, respectively.
5/1/2017
Examples:
 Only the (-) enantiomer of epinephrine has the
OH group in the binding site, and therefore has a
much more potent pressor activity.
5/1/2017
▪ Enantiomers interact with living systems in very
different ways and results for example in:
− Different smell
CH3
CH3
O
O
(S)
(R)
H2C
H
H
CH3
CH2
H3C
(R) Spearmint oil
(S) caraway oil
Mirror plane
5/1/2017
Olfactory sensors are chiral
− Different taste
Aspartame
O
O
O
H
H
O
O
N
H3N
O
O
CH3
H
H
H3N
O
H
(R,R)
160 Times Sweeter
than Sugar
Bitter!!
Taste buds are chiral
5/1/2017
O
N
O
(S,S)
H
CH3
− Different drug effects
• Biomolecules, thus, can discriminate between
enantiomers (isomers) of a given drug molecule.
• The net result is same or different pharmacologic/
pharmacokinetic/ toxicologic activities
5/1/2017
Biological Discrimination
=>
5/1/2017
THALIDOMIDE: DISASTROUS BIOLOGICAL
ACTIVITY OF THE “WRONG” ENANTIOMER
H
H
N
N
*
H
O
(R)-isomer
O
O
N
O
O
N
*
O
O
H
O
(S)-isomer
− In the 1960’s thalidomide was given as racemic mixture
(RS) to pregnant women to reduce the effects of morning
sickness.
− This led to many disabilities in babies and early deaths in
many cases.
The photographs are both from ‘Molecule of the Month’ at Bristol University:
5/1/2017
http://www.chm.bris.ac.uk/motm/thalidomide/start.html
− Later found that only the R-isomer can be used safely
− In 1998 thalidomide has been approved by FDA to
reduce the immune system’s inflammatory response in a
host of illnesses, including arthritis, lupus, cancer,
leprosy, and AIDs.
5/1/2017
O
NHCH3
CH3NH
O
H
H
CF3
CF3
(S)-Fluoxetine
(R)-Fluoxetine
− The pure S enantiomer prevents migraines.
− A racemic mixture of fluoxetine (sold
antidepressant Prozac) doesn’t prevent migraines.
HOOC
OH
HO
(S)
(S)
C
H2N
as
the
COOH
C
Copyright© 1999, Michael J. Wovkulich. All rights reserved.
H
H
OH
L-Dopa
Anti-Parkinson’s
5/1/2017
disease drug
NH2
HO
D-Dopa
Biologically inactive
has serious side effects
 Likewise, cis/trans isomers of cyclic compounds,
or Z/E isomers of alkenes are also expected to
have different binding potency and therefore also
different biological activity.
5/1/2017
5/1/2017
OH
OH
HO
HO
HO
E-DES
(Active)
Estradiol
Z-DES
(Inactive) OH
OH
OH
HO
Estradiol & E-DES overlay
5/1/2017
 According to this theory, the "right" isomer is
called the eutomer.
 The "wrong" isomer is called the distomer.
 The ratio of the activities of the eutomer and
the distomer is called the eudismic ratio, and
converting the equation to log form affords the
eudismic index, EI.
5/1/2017
 Acetylcholine may interact with the muscarinic
receptor of postganglionic parasympathetic nerves
and with Acetylcholine esterases in the fully
extended confirmation and in a different morefolded structure with the nicotinic receptors at
ganglia and at neuromuscular junctions.
– Gauche conformer = muscarinic
– Anti conformer
= nicotinic
5/1/2017
 Conformation is a spatial arrangement of a
molecule of a given constitution and configuration.
5/1/2017
Life is Chiral
COOH
COOH
C
R
H
NH2
C
R
H
NH2
• Proteins are built from L-amino acids, which implies
that enzymes - the catalysts of nature - are chiral
• Consequently, most biomolecules are chiral (sugars,
DNA, proteins, amino acids, steroids)
• Also, receptors (drug, taste, biopharmaceuticals,
agrochemicals) are chiral and the natural ligand to a
receptor is often only one specific enantiomer
• This is why mirror image molecules can have radically
different
activities (effectivity, toxicity, taste) in the
5/1/2017
body.
Stereochemistry
Ph
Ph
HC
OH
HC
NHCH3


CH
H
C NH
HO
CH
H3CHN
CH
CH3
CH3
CH3
Ephedrine
Ph
Ph
HO
HC
CH
HC
H3CHN
NHCH3
o
(mp = 76 C, []D = -50 )
H2
C
N+
H
H
C
OH
OH
5/1/2017
X
Receptor
-(-)-Epinephrine
Ephedrine (more
active)
- more
active
Diastereoisomers: Optical isomers
which are not mirror images
–
Racemates: Mixture of equal parts
of enantiomers
CH
Pressor activities of ephedrines
Isomer
H
OH
Anionic
site
–
OH
L(+) Pseudoephedrine
D(-) Pseudoephedrine
H 3C
isomers
CH3
CH3
o
Enantiomers:
Optical
which are mirror images
L(+) Ephedrine
D(-) Ephedrine
(mp = 40oC, []D = -6o)
OH CH3
–
Flat
Area
D (-) Pseudoephedrine
DL Pseudoephedrine
L (+) Pseudoephedrine
L (+) Ephedrine
DL Ephedrine
D (-) Ephedrine
Relative Activity
1
4
7
11
26
36