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III. Pharmacodynamic Phase

Nature of Receptors
1. Pure Proteins (Enzymes) Several Drugs (Mostly Inhibitors) Are
Designed to Target the Active Sites of Certain Enzymes
2. Nucleic Acids DNA Double Helix Contains Receptors for Some Drugs
3. Lipids Sometimes Lipids May be Regarded as Receptors
4. Lipoproteins or Glycoproteins Are the Most Common Types of
Receptors They Are Often Embedded in The Cell Membrane
(Adrenergic And Cholinergic Receptors). Other Receptors Are Located
within the Cell.
The Capability of A Drug to Adapt itself
to React with A Receptor Depends on:
➢ The Structure, Configuration and Conformation of both
Drug and Receptor
➢ Bonds and Forces Involved for this Adaptation
1

Bonds and Forces Involved in Drug-Receptor Interactions

1- Covalent Bond
➢ The Strongest Bond (50–150 Kcal/Mol)
➢ Few Drugs Form Covalent Bonds with Receptors
➢ Drug Leaves Receptor when its Concentration Decreases in Extracellular Fluid
a. Penicillin Acylates Transpeptidase Enzyme of Bacteria Forming Covalent Bond
Thus Preventing Cell Wall Formation
H H H H H H
S NU S
R N R N
+
N HN
O O O O
COOH Transpeptidase NU COOH
Enzyme

b. Nitrogen Mustards (Anticancer) Cl NU

NU
Alkylate Nucleophilic Targets
on Double Helix of DNA R N + 2 R N

Cl NU
2

2. Electrostatic Bonds
Drugs Are Attracted to their Receptors by these Forces
i. Ionic Bond R4-N+……I-
➢ Bond Strength is 5-10 Kcal/Mol
➢ At Physiological pH Basic Drugs Are Protonated to be Positively Charged
➢ Acidic Drugs Are Deprotonated to be Negatively Charged
➢ Attraction Occurs Between Opposite Charged Species of Drug and Receptor
H -
O
ii. Reinforced Ionic Bond +
R N H C
➢ Bond Strength Is 10 Kcal/Mol
H O
iii. Ion-Dipole Interaction
➢ Bond Strength is 1–7 Kcal/Mol -
➢ The Presence of An Electronegative Atom (O, N, S, Halogen) + O
Relative to C Leads to Asymmetric Distribution of Electrons R NH3
and Formation of Dipole Moiety Attraction Would then Occur +
with An Ion

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- +
iv. Dipole-Dipole Interaction O C
➢ Bond Strength is 1–7 Kcal/Mol
➢ Dipoles in A Drug Molecule Can be Attracted by C N
Complementary Dipoles of Receptor + -

v. Charge-Transfer Complexes
➢ Bond Strength is 1–7 Kcal/Mol
➢ Occurs Between An Electron Rich and Electron Deficient Molecules

3. Hydrogen Bond
➢ Bond Strength is 1–10 Kcal/Mol
➢ May Be Intermolecular or Intramolecular
➢ Important in Drug-Receptor Interaction
➢ Essential in Maintaining Structural Integrity of Proteins and Nucleic Acids

4. Van der Waal’s Forces

➢ Bond Strength is 0.5–1 Kcal/Mol
➢The Aromatic Ring (in Most Drugs) has this Type Of Attraction
The Flat Ring Fits to A Complementary Flat Area
➢This Force is Also Formed Between A Linear Aliphatic or A Small Branched
Chain of A Drug and A Complementary Part on A Receptor

5. Hydrophobic Interaction
➢ Bond Strength is 1 Kcal/Mol.
➢ Important Force Created Between Non-Polar Regions of Drug and Receptor
➢ The Nonpolar Regions Are Separated By Water Molecules that Associate by
H Bonding to Form Quasi-Crystalline Structures Or Iceberg
➢ When Non-polar Regions (Hydrocarbon Chain of Drug and Receptor) Come
Close, Water Molecules Are Collapsed Producing A Gain in Energy which
Stabilizes the Close Contact of the Nonpolar Regions

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Stereochemistry and Drug-Receptor Interactions

➢ Steric Factors of Drug And Receptor Determine the Nature and
the Efficiency of Drug-Receptor Interaction
➢ Steric Factors Include:
1. Rigidity of the Molecule 2. Geometric Isomerism
3. Conformational Isomerism 4. Optical Isomerism
5. Molecular Dimensions and Interatomic Distances

2. Geometric Isomerism
➢ Molecules with Restricted Rotation as in Olefinic Structures
➢ Isomers May Have Different Physical and Chemical Properties
➢ So Different Distribution in Biological System
➢ Different Interaction with A Specific Receptor
OH
OH HO OH

HO HO

Estradiol (Natural Hormone) Trans Diethylstilbestrol Cis Diethylstilbestrol

Active 14 Times Than Cis Less Active Than Trans 7

3. Conformational Isomerism
➢ Isomers Exist at Different Arrangements in Space Due To Free Rotation
Around Single Bond Permitting Interconversion of Isomers and
Have Many Conformers
➢ Energy Barrier Between Different Conformers Would Affect their
Interconversion And their Relative Concentration is in the Medium
a. Conformation Of Acyclic Structures
➢ Flexibility of Open Chain Molecules (Acetylcholine, Histamine) Permit
Different Conformations that Are Able to Interact with Different Receptors
Giving Multiple Biological Effects O
N(CH3)3
➢ Acetylcholine acts at the Muscarinic and at the H3C O
Nicotinic Receptors Fully Extended
N(CH3)3 N(CH3)3 N(CH3)3 N(CH3)3
OCOCH3
H H CH3OCO H H OCOCH3

H H
H H H H H H
H H
OCOCH3 H H
Staggered (Transoid) Skew Gauch Eclipsed Cisoid
(Favored) (Less Favored) 8

b. Conformation of Cyclic Structures a

e a
➢ Substituent Attached to Axial Positions is Susceptible a e
to Steric Crowding e e
➢ 1,3-Diaxial Substituents Larger than H Repel Each
e a a
Other Twisting the Flexible Ring and Placing the
e
Substituents in the Less Crowded Equatorial Cylclohexane
Conformation a
➢ Usually An Equilibrium Mixture of Conformers Exists

4. Optical Isomerism
i. Enantiomers, Enantiomorphs, Optical Antipodes

Compounds Having 1 Asymmetric Carbon Atom Mirror Images,

Non Superimposable Identical Physical and Chemical Properties
Rotate the Plane of Polarized Light Differently
May Show Different Biological Activities
One May Be Active, Less Active, Inactive or Toxic
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Easson-Stedman’s Hypothesis
“A Biologically Active Enatiomer Will Have A Good Fit on Receptor by
3 Point Attachments and is Called Eutomer, the other Isomer Will Fit by Only
2 Point Attachments and is Called Distomer and Expected to be Less Active”
➢ Levo (-) Epinephrine (High Pressor Activity) Shows 3 Binding Groups
➢ Dextro (+) Epinephrine (Low Pressor Activity) Shows Only 2 Binding Groups
➢ Deoxyepinephrine (Lacks OH) Has Low Pressor Activity As (+)-Epinephrine
H OH

H N OH H N OH

H OH H H
OH OH

Anionic X Anionic X
Flat Area Flat Area
Site Cationic Site Cationic
Site Site
(-) Epinephrine (Highly Active) (+) Epinephrine (Low Activity)

10

ii. Diastereoisomers, Diastereomers

➢ Compounds with 2 or More Asymmetric Centers
➢ Have Same Functional Groups but Occupy Different Relative Positions
➢ Undergo the Same Chemical Reactions but at Different Rates
➢ Not Mirror Images and Have Different Physical Properties And Activities
➢ May Differ in Distribution, Metabolism and Interaction with Receptor
➢ One Isomer May be Active, May Cause Side Effects, May be Toxic or Inactive
(1R,2S)-(-) Ephedrine (1S,2R)-(+) Ephedrine
[(D)(-)Ephedrine] [(L)(+)Ephedrine]
Ephedrine Has 2 Chiral C, H H
And 4 Isomers HO N HO N
D-(-)Ephedrine H H H H
1 2 1 2
(Bronchodilator,
Analeptic, Vasopressor, R= Rectus
S= Sinister
And Antiasthmatic) H H
L-(+) Pseudoephedrine HO N HO N
(Nasal Decongestant, H H H H
1 2 1 2
Bronchodilator,
And Less Pressor Activity)
(1R,2R)-(-) Pseudoephedrine (1S,2S)-(+) Pseudoephedrine
[(D)(-)Pseudoephedrine] [(L)(+)Pseudoephedrine]11

5) Molecular Dimensions And Interatomic Distances

➢ Receptors Are Mostly Protein in Nature.
R H O
➢ 3.61Å is the Distance Between 2 Peptide Bonds H
when Maximally Extended (Identity Distance) N
N N
➢ 3.61Å Or its Multiples Are Found in Many Drugs H
H O R H
➢as Acetylcholine Derivatives 7.2Å (3.61 X 2)
Between the Ester Carbonyl and N
➢ Distance Between OH Bonding in Estrogens is
3.61A
14.5Å (3.61 X 4)
5.5Å Corresponds to Distance Between 2 Turns of -Helical Structure Common
to Proteins and Found Between Functional Groups of Many Drugs
(Local Anesthetics, Antihistamines)
5.5A

O
N

Diphenhydramine
(Antihistaminic)
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➢ Sulfonamides and p-Aminobenzoic Acid Have Close Structural Resemblance in

Planarity And Interatomic Distances
➢ Sulfonamides Can Occupy the Surface of Dihydropteroate Synthetase Enzyme
So no Folic Acid Formation
➢ Dihydropteroate Synthetase Enzyme Has 2 Binding Sites
One Specific for NH2, the Second is Non Specific Ionic Site

NH2 NH2

6.7A 6.9A

C S
O OH O O
NHR
2.3A 2.4A

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Theories of Drug-Receptor Interactions

➢ The Drug Binds to Receptor then Acts to Initiate A Response (Agonist) or

Decrease Activity of Receptor (Antagonist) by Blocking any other Access
➢ The Drug-Receptor Interaction is Reversible and is Governed by the
Law of Mass Action

1. The Occupation Theory

➢ The Intensity of A Pharmacological Action is Directly Proportional to the
Number of Receptors Occupied by the Drug
➢ The Number of Receptors Occupied is Dependant on the Concentration of the
Drug in A Unit Area or Volume
➢ A Maximal Effect is Achieved when All Receptors Are Occupied
➢ The Effect Stops when the D-R Complex Dissociates

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2. Arëns (1954) And Stephenson’s Modification (1956)

➢ Drug-Receptor Interaction Comprises 2 Steps:
a. Reaction of the Drug with the Receptor (Affinity)
b. Production of An Effect (Efficacy or Intrinsic Activity)
➢ Both Agonist and Antagonist Have Affinity to A Receptor Forming D-R
Complex
➢ Agonist Only Gives Rise to Stimulation (Efficacy or Intrinsic Activity)
➢ The Theory Does not Indicate why Agonists Are Active & Antagonists Are
not Although they Occupy the Same Receptor
3. Rate Theory
➢ Activation of Receptors is Proportional to the Total Number of Encounters of
Drug Molecules with Receptors per Unit Time
➢ Pharmacological Activity is A Function of the Rate of Association and
Dissociation (not the Number of Occupied Receptors)
➢ Agonist Has Fast Association and Fast Dissociation with the Receptor
➢ Antagonist Has Fast Association and Slow Dissociation with the Receptor
➢ Partial Agonist Has Intermediate Association and Dissociation with the Receptor
➢ Limitation Agonist Binds Less Tightly Than Antagonist !!!!
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4. The Induced Fit Theory

➢ The Drug Approaches the Receptor and One or Both Alter Conformation of
Binding Sites to Create D-R Complex. This Process is Called Induced Fit

5. Macromolecular Perturbation Theory

➢ Binding of A Drug to its Receptor Can Lead to Either:
a. Specific Conformational Perturbation Leading to A Pharmacological
Response (Agonist)
b. Nonspecific Perturbation which Will not Initiate A Response (Antagonist)

6. Activation-Aggregation Theory
➢ An Extension of the Macromolecular Perturbation Theory
➢ The Receptor is in A State of Dynamic Equilibrium Between Active (Ro)
and Inactive (To) Forms (as 2 Conformations Even when the Drug is Absent)
➢ An Agonist Shifts the Equilibrium to Active Form
➢ An Antagonist Shifts the Equilibrium to the Inactive Form
➢ A Partial Agonist Favors both States

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Isosterism And Bioisosterism

1. Isosterism
➢ Replacement or Modification of A Functional Group with Another
Group Having Similar Properties

(1919)
➢ Isosteres Are Compounds or Group of Atoms which Are not Isomeric
but Have the Same Number And Arrangements of Electrons and Same
Total Charge (Isoelectric)
➢ They also Have Similar Physical Properties
N2 and CO (14 Total Electrons) N3- and NCO- CO2 And N2O

17

(1925)
➢ Addition of A H Atom with its Electron (Hydride) to An Atom,
Produces A Pseudoatom
➢ Pseudoatoms Show Some Similarity in Physicochemical Properties as
Atoms Having the Same Number of Electrons (Total Electron Count)

6 7 8 9 10
C N O F CH4
CH NH OH FH
CH2 NH2 OH2
CH3 NH3

➢Some Groups May Show Similar Physical or Chemical Properties But Not
General as in Case of OH and NH2 Both Form H Bonding
➢ At Physiologic pH, OH is Neutral while NH2 is Basic
NH2 Imparts A +ve Charge to the Molecule
➢ The Law Failed to Take into Account Other Physicochemical Parameters

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(1948)
➢ Atoms, Ions or Molecules Having the Same Number of Peripheral Electrons
Are Isosteres (Electrons on the Outer Most Orbital)
➢ This Include Elements in the Same Group of the Periodic Table (O, S, Se…)
and the Pseudoatoms Related with the Same Number of Peripheral
Electrons (NH, CH2)
➢ With Increased Understanding of the Structures of Molecules, Less Attention
was Focused on the Number of Electrons Involved
➢ Broader Definition Isosteres Includes Groups which Possess Similar Steric
and Electronic Configurations Regardless of the Number of Electrons
Involved

Applied the Term "Ring Equivalent" for Isomerism to the Entire Molecule
➢ In Aromatic Ring Systems Some Groups Could be Exchanged without
Severe Changes in Physicochemical Properties
➢ Benzene, Thiophene and Pyridine Are Examples

S N 19

2. Bioisosterism
➢ Bioisosteres are Groups with Similar Physicochemical, Steric and Electronic
Properties and Imparting Similar Biological Properties to A Compound
(Agonists Or Antagonists)

Classical And Nonclassical Bioisosteres

➢ Alfred Burger (in 1970) Divided Bioisosteres into 2 Categories:

1. Classical Bioisosteres
➢ Are Functional Groups that Satisfy the Previous Electronic Definition
➢ Monovalent Functional Groups as –F, -OH, -NH2, -CH3, -Cl, -Br, -SH
➢ Bivalent Functional Groups as =CH2, =NH, -O-, -S-, -Se-
➢ Trivalent Functional Groups as –CH=, -N=, -P=, -As=

2. Nonclassical Bioisosteres
➢They Do Not Obey Definitions of Classical Bioisosteres, They Do Not
Necessarily Have the Same Number of Atoms as the Substituent they Replace

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Most Common Bioisosteric Replacements

S N
Phenyl Thiophenyl Allyl Cyclopropylmethenyl
Pyridyl

H O O
OH N OH
S
O O O
Carboxyl Carbamoyl Carbonyl Sulphonyl

-COO- and –SO2-N-R; C=O and S=O; Halogen, CF3, and CN

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Bioisosterism as A Useful Strategy for Molecular

Modification in Drug Design
➢ Structural Alteration of A Drug through Isosteric Replacement of Atoms or
Groups May Lead to A New Drug with More Selective Bioactivity, Less
Toxicity and Improved Pharmacodynamic And Pharmacokinetic Properties
➢ In Some Cases this Replacement May Lead to An Antagonist
1. Replacing the CH3 Group in Acetylcholine with NH2 Group Gives
Carbachol (Agonist) Which is Less Susceptible To Hydrolysis
O O
N N
O H2N O
Acetylcholine Carbachol
2. Replacement of A H in Uracil with F 3. Replacement of OH in Hypoxanthine
Gives 5-Fluorouracil (Antineoplastic) with SH gives 6-Mercaptopurine
O O (Antineoplastic)
OH SH
H H H F
N N N N
N N

O N O N N N N
N
H H H Metabo
H
Uracyl 5-Fluorouracil 6-Mercaptopurine
lism
Hypoxanthine
(Metabolite) (Antimetabolite) (Antimetabolite) 22
(Metabolite)