Physicochemical Principles of Drug Action

Physicochemical Principles of Drug ActionPhysicochemical Principles of Drug Action

Associate Prof. Magdi A. Mohamed, Faculty

of Pharmacy, University of Khartoum (2014)1

• To design better drugs:

� Molecular Mechanism.

Functional group contributions to the� Functional group contributions to the

physicochemical properties.



• Drug action results from the interaction of

drug molecules with either normal or

abnormal physiological processes.

• Drugs normally interact with targets (which

they are proteins, enzymes, cell lipids, or

pieces of DNA or RNA).pieces of DNA or RNA).

• The ability of a chemical compound to elicit a

pharmacologic /therapeutic effect is related to

the influence of its various physical and

chemical (physicochemical) properties



Physicochemical Principles of Drug Action

• The influence of the organic functional groups

within a drug molecule on:

� Water solubility.

� Lipid solubility.� Lipid solubility.

� Partition coefficient.

� Acid-base properties.

� Steric factors.

� Stereochemistry.



• Proper physicochemical parameters ensure

good drug action:

� Pharmacokinetic properties.� Pharmacokinetic properties.

� Pharmacodynamic properties.



• Pharmacokinetic properties:

� Absorption.

� Distribution.

� Metabolism.

� Excretion.� Excretion.

• Pharmacodynamic properties:

� Drug-receptor interaction:

o Activity.

o Toxicity.



Water solubility Versus Lipid solubility

• Majority of drugs’ molecules possess balanced

solubility (have some degree of solubility in

both aqueous and lipid media).

• Because there is a need for drugs’ molecules• Because there is a need for drugs’ molecules

to move through both aqueous (plasma,

extracellular fluid, cytoplasm, etc.) and lipid

media (biologic membranes) in the biological

system.





Most Important Intermolecular Attractive

forces Involved in Solubilization

• Van der Waals attraction.

• Dipole-dipole attraction.• Dipole-dipole attraction.

• Ion-dipole bonding.



Van der Waals Attraction

• Weakest intermolecular force (0.5-1.0

kcal/mole)

• Electrostatic• Electrostatic

• Occurs between nonpolar groups (e.g.

hydrocarbons) .

• Highly distance and temperature dependent.



Dipole-Dipole Attraction

• Stronger (1.0 to 10 kcal/mole).

• Occurs electrostatically between electron

deficient and electron excessive/rich atoms

(dipoles).

• Hydrogen bonding is a specific example of this

bonding and serves as a prime contributor to

hydrophilicity.





N

H

O

H

H

OHH



NH

HOH

R OH

R

O

R`

R NH2

R NH

Functional Groups Number of Potential H-bonds

3

2

3



R NH

R`

R N R``

R`

R

O

OR`

2

1

4

O O

O

O O

OH

less water solube more water solube

H

H

H



• Why does an intramolecular hydrogen

bonding decrease water solubility?

• Because one less interaction with solvent

occurs.

less water solube more water solube

Ion-Dipole Bonding

• Electrostatic between a cation/anion and a

dipole.

• Relatively strong (1-5 kcal/mole).• Relatively strong (1-5 kcal/mole).

• Low temperature and distance dependence.

• Important attraction between drugs’ molecule

and H2O.





• Highly dissociable salts are more water soluble

than less dissociable ones.

• Because the cation and anion must be able to

separate and interact with water molecules.

• Highly dissociable salts are formed from:

� strong acids with strong bases.



� strong acids with strong bases.

� weak acids with strong bases.

� strong acids with weak bases

• Less dissociable salts are formed from:

� weak acids with weak bases.



N

O

S

H3C CH3

COO

OO

N

H

HN

N

O

S

H3C CH3

COO

HN

Na



NH2

O O

(Water solubility = 1g/250ml) (Water solubility = 1g/40ml)





• Why is the amino acid tyrosine less water

soluble than expected?

• The ionizable functional groups can react with

one another to form a zwitterionic molecule.

HO

COO

NH HH



one another to form a zwitterionic molecule.

• The two opposite charges are sufficiently close

to allow a strong ion-ion interaction to form.

• Thereby keeping each of these groups from

forming ion-dipole interaction with

surrounding water molecules.Associate Prof. Magdi A. Mohamed, Faculty


• Solubility of tyrosine in water, aqueous base,

and aqueous acid.

Prediction of Relative Solubility

• The relative solubility of a drug molecule is a

function of the presence of both lipophilic and

hydrophilic features within its structure, which

serve to determine the extent of interaction of

the drug molecule with lipid and/or aqueous



the drug molecule with lipid and/or aqueous

phases.

• Therefore, the relative solubility of a drug

molecule is the sum of the contributions of

each group and substituent to overall

solubility.

Laboratory Estimation of Relative

Solubility

• The relative solubility of a drug molecule can

be determined in the laboratory.

• The ratio of the solubility of the compound in



• The ratio of the solubility of the compound in

an organic solvent to the solubility of the

same compound in an aqueous is called

partition coefficient (P).

• Partition coefficient (P) is a measure of the

solubility of a drug in aqueous and lipid

phases.

• Simulation.



• Determined in vitro.

• n-Octanol (lipid phase)

• Phosphate buffer of pH 7.4 (aqueous phase).

• P is often expressed as a log value.Associate Prof. Magdi A. Mohamed, Faculty


Mathematical Estimation of Relative

Solubility

• Solubility contributions (groups and

substituents) are expressed as hydrophilic

(negative value) or lipophilic (positive value)

fragment constants.



fragment constants.

Log Pcalc = Σπ

• Where; Log Pcalc = log of partition cofficient

and Σπ = sum of hydrophilic-lipophilic

constants.

Mathematical Estimation of Relative

Solubility

(i) the molecule is dissected into its various

groups, functionalities and substitutents,

(ii) appropriate hydrophilic/lipophilic fragment

constants are assigned and summed, and

(iii) compounds with log Pcalc values greater



(iii) compounds with log Pcalc values greater

than +0.5 are considered water insoluble

(lipophilic, solubility is less than 3.3% in

water) and those with log Pcalc values less

than +0.5 are considered water soluble

(hydrophilic).

Hydrophilic-Lipophilic Fragment Constants

(π)

• Measures the hydrophobicity of a specific

region on the drug.

• Log P is measured experimentally for astandard compound with and without asubstituent (X).substituent (X).

• The following equation is used:

πx = log Px — log PH

• Positive π = X more hydrophobic than H.

• Negative π = X less hydrophobic than H.Associate Prof. Magdi A. Mohamed, Faculty


Hydrophilic-Lipophilic Fragment Constants (π)

ππππ ValueFragment

+0.5C (aliphatic)

+2.0C6H5-

+0.5Cl

+0.2O2NO

+0.65Intramolecular hydrogen bonding (IMHB)



+0.65Intramolecular hydrogen bonding (IMHB)

0.0S

-0.7O=C-O

-0.7O=C-N

-1.0O(hydroxyl, phenol, ether)

-1.0N (amine)

-0.85O2N (aliphatic)

-0.28O2N (aromatic)



π Values For Various Substituents on Aromatic Rings

ππππ ValueSubstituent

+0.52CH3

+1.68t-Bu

-0.67OH

-1.49CONH2



-1.49CONH2

+1.16CF3

+0.71Cl

+0.86Br

+0.14F

• Log P for benzene = 2.13.



• Prediction: water insoluble.

Impact of Partition Coefficient On Drug

Action

• The relative solubility of a drug molecule

greatly affects:

� Routes of administration.� Routes of administration.

�Absorption.

� Distribution.

� Elimination.



• Higher or smaller values of (Log P):

� Solubility in plasma (distribution).

� Lipid barriers (brain and neuronal tissues).� Lipid barriers (brain and neuronal tissues).

� Trapping (first site of loss).



HN

O

CH3

O NH

OH

CH3

CH3

O NH

OH

CH3

CH3

Propranolol ( -blocker)

• Contrary to propranolol, practolol has no CNS

side effects.

• Drugs with Log P values close to 2 should be

able to enter the CNS efficiently.Associate Prof. Magdi A. Mohamed, Faculty


O

Practolol ( -blocker)

Propranolol ( -blocker)

Overton-Meyer Hypothesis

• Relation between physicochemical properties

and drugs action (theories).

• Based on the observation that neutral and

lipid soluble substances have a depressantlipid soluble substances have a depressant

effect on neurons.

• It states that, for these compounds, the higher

the partition ratio P, the higher the

pharmacological effect.



The Ferguson Principle

• Extended theory (for all drugs).

• The concentration (molarity or partial• The concentration (molarity or partial

pressure) of a drug in plasma is directly

proportional to its activity.



The Ferguson Principle

Pt

P0

= X orSt

S0= X

Where:

Pt is partial pressure required for a pharmacological effect, and

P0 is the partial pressure of the pure substance.



or

St is the molar concentration required for a pharmacological effect, and

S0 is the molar solubility of the compound.

X = 1 to 0.1 means the drug has high thermodynamic activity.

X < 0.1 means the drug has low thermodynamic activity.

• High thermodynamic activity (X = 0.1 to 1)

means :

the activity of the drug is based on its physical

properties only (e.g. gaseous anesthetics).properties only (e.g. gaseous anesthetics).

• Low thermodynamic activity (X < 0.1) means:

the activity of the drug is based on its

structure rather than its physical properties.



• Depending upon the degree to which chemical

structure affects biological action, drugs can

be classified as:

� Structurally non-specific (X = 0.1 to 1).

� Structurally specific (X < 0.1).



Structurally Non-specific Drugs

• They have no specific site of action.

• The activity does not depend on chemical

structure.

• The activity depends on physical properties.

• Minor modifications do not affect the activity.• Minor modifications do not affect the activity.

• Effective only in high concentrations.

• Examples of these drugs are gaseous

anesthetics (diethyl ether, N2O, CHCl3), some

sedative and hypnotics and many antiseptics

and disinfectants.Associate Prof. Magdi A. Mohamed, Faculty


Structurally Specific Drugs

• They act at specific sites, such as a receptor or

an enzyme.

• Biological action is related to the chemical

structure.structure.

• Minor alterations in groups in parent structure

bring about appreciable difference in activity.

• Effective in a relatively low concentration.

• Stereoisomers differ greatly in activity.







Acid-Base Properties

• Absorption:

� Un-ionized form (lipid soluble).

• Distribution:

� Ionized form (soluble in plasma).� Ionized form (soluble in plasma).

• Excretion.

• Drug-Receptor interaction.

• Drug-Drug incompatibility.



CH3COOH + H2O CH3COO H3O+

acid base conjugate conjugate

• Bronsted-Lowery theory.

• Proton donor (acid).

• Proton acceptor (base).



acid base conjugatebase

conjugateacid

CH3COOH + H2O CH3COO H3O+

acid base conjugate conjugate

• Ionized forms are water-soluble.

• Unionized forms are lipid soluble.



acid base conjugatebase

conjugateacid

Acidic Functional Groups



Basic Functional Groups



Neutral Functional Groups

R OH

alkyl alcohol

ROR1

ether

O O

R C N

nitrile

HO



R OR1

O

ester

R NH2

O

amide

HN

diarylamine

R

O

R1

ketone &aldehyde

Electronic Effects of Substituents

• The electronic effects of various substituents

will clearly have an effect on a drug’s

ionization or polarity.

• This in turn may have an effect on how easily a• This in turn may have an effect on how easily a

drug can pass through cell membranes or how

strongly it can bind to a receptor.

• It is therefore useful to have some measure of

the electronic effect a substituent can have on

a molecule.



The Hammett Substitution Constant (σx)

• Is a measure of the electron withdrawing or

electron donating ability of a substituent on

the molecule.

• For the effect of substituent on an aromatic• For the effect of substituent on an aromatic

ring, the Hammett constant (σx) is used.

• This constant has been determined by

measuring the ionization of a series of

substituted benzoic acids compared to the

ionization of benzoic acid itself.






• The value of σx for an electron withdrawing

substituent (e.g. Cl, CN, CF3, NO2) is positive.

• The value of σx for an electron donating• The value of σx for an electron donating

substituent (e.g. Me, Et, t-Bu) is ngative.

• The Hammett substituent constant for H is

zero.




• The Hammett constant takes into account

both resonance (R) and inductive effects (F).

• Therefore, the value of σ for a particular

substituent will depend on whether thesubstituent will depend on whether the

substituent is meta or para.

• This is indicated by the subscript m or p after

the σ symbol.




• The nitro group has two values for σ.

�For para position, σp is 0.78.

�For meta position, σm is 0.71.m

• The hydroxyl group has two values for σ.

�For para position, σp is −0.37.

�For meta position, σm is 0.12.



para Nitro group – electronic influence on R is due

meta Nitro group – electronic influence on R is inductive.



para Nitro group – electronic influence on R is due

to inductive and resonance effects.

R

NOO

R

NOO

R

NOO

R

NOO

para Hyroxyl group – electronic influence on R

meta Hydroxyl group – electronic influence on R is

inductive.

OH

R



para Hyroxyl group – electronic influence on R

dominated by resonance effects.

• Ciprofloxacin, a fluoroquinolone antibiotic.



• Ciprofloxacin, a fluoroquinolone antibiotic

• Both acidic and basic properties (amphoteric).



• Once in GIT, it behaves as an acid or a base.

• Factors:

pH (variable).� pH (variable).

� pKa (constant).





• Drugs pass through membranes in an un-

ionized form.

• Drugs act as ions (if ionization is a possibility).• Drugs act as ions (if ionization is a possibility).

• Ideal pKa (6-8; weak acid or weak base).

• Assumption passive diffusion.



Predicting the Degree of Ionization: Acids

• Henderson-Hassalbach equation.



pKa = pH + log[Cunionized]

[Cionized]

8 = 7.4 + log[Cunionized]

[Cionized]

0.6 = log[Cunionized]

[Cionized]

HN

HN

O

O

O

amobarbitalpKa = 8

HN

O

O



[Cionized]

10 0.6 =[Cunionized]

[Cionized]=

3.98

1

% unionized =3.98 x 100

4.98= 79.9%

N

O

O

HN

N

O

O

O

Aspirin

• An orally administered drug (pKa = 3.5).

• Acidic stomach.

� Partial absorption (un-ionized form).

• Basic intestinal tract.• Basic intestinal tract.

� Ionized form.

� Microvilli.

� Huge surface area.

� Absorption.Associate Prof. Magdi A. Mohamed, Faculty


• pK = 3.5.



• pKa = 3.5.

• Oral route.

• Absorbed in

stomach.

Predicting the Degree of Ionization: Bases

• Henderson-Hassalbach equation.



• Amines (pK 9-10).

BH + H2O B H3O+

conjugateacid

(basic pH)

absorbed

• Amines (pKa 9-10).

• BH+ is not absorbed (stomach).

• Alkaline intestinal tract (pH ≈ 8).

• Equilibrium.

• B and BH+ are absorbed.



Acid-Base Chemistry/ Compatibility

N

SH H

NH

O

O

OCOO K

CH3

CH3

O

OH

HN

H3CHH

H2PO4

• What is the chemical consequence of mixing

aqueous solutions of of these two drugs in the

same IV bag?Associate Prof. Magdi A. Mohamed, Faculty


Penicillin V Potassium

Codeine Phosphate

H3CO

O• K+/H+ ATPase inhibitor.• K+/H+ ATPase inhibitor.

• Used for treatment of peptic ulcer.

• pKa ≈ 4 (not protonated in the stomach).

• Can be absorbed into the parietal cells.

• Is protonated inside the parietal cells (pH < 1).



N

O

S

O

NH

N

O

H ATPase

N

O

SN N

N

O

SN NH S

ATPase



NH

omeprazole

A





Steric Properties

• For a drug to interact with an enzyme or a

receptor, it has to approach, then bind to a

binding site.

• The bulk size, and shape of the drug may have

an influence on this process.an influence on this process.

� For example, a bulky substituent may act like a shield

and hinder the ideal interaction between drug and

receptor.

� Alternatively, a bulky substituent may help orientate

a drug properly for maximum receptor binding and

increase activity.Associate Prof. Magdi A. Mohamed, Faculty


Measuring Steric Properties

• Quantifying steric properties is more difficult

than quantifying hydrophobic (P and π) or

electronic properties (σ).

Several methods have been tried, e.g.:• Several methods have been tried, e.g.:

� Taft’s steric factor (Es).

� Molar refractivity (MR).

� Verloop steric parameter.



Quantitative Structure-Activity

Relationship (QSAR)

• Attempts to identify and quantitate

physicochemical properties of a drug in

relation to its biological activity or binding.

• Study hydrophobic, electronic, and steric• Study hydrophobic, electronic, and steric

properties (either whole molecule or pieces).

• Medicinal chemist draws up an equation that

quantifies the relationship & allows one to

predict (to some extent) the biological activity.



Hansch Equations

• Relate biological activity to the most

commonly used physicochemical properties:

(P and/or π, σ, and a steric factor)(P and/or π, σ, and a steric factor)

• Not all these parameters will necessarily be

significant.



Example-1

• The adrenergic blocking activity was related to

π and σ and did not include a steric factor.

• The substituents should be hydrophobic (+π)

and electron donating (−σ).



Example-2

• The QSAR equation indicates that inhibitory

activity was related to π, σ and steric factor.



Substituent π σm σp Es

-CN -0.57 0.56 0.66 -0.5

-Cl 0.71 0.37 0.23 -0.9

-OH -0.67 0.12 -0.37 -0.5



-OH -0.67 0.12 -0.37 -0.5

-NH2 -1.23 -0.16 -0.66 -0.6

-phenyl 1.96 -0.06 -0.01 -3.8

-C3H7 1.55 -0.07 -0.13 -1.6

• Calculate the IC50 values when X is:

� -NH2.

� -phenyl.

� -CN.Associate Prof. Magdi A. Mohamed, Faculty


Stereochemistry & Drug Action

• Stereoisomers:

� Similar MF.

� Same connectivity of atoms.

� Different three-dimensional structures.

• Two types:• Two types:

� Configurational isomers:

o Enantiomers.

o Diastereoisomers.

� Conformational isomers.Associate Prof. Magdi A. Mohamed, Faculty


• Physicochemical properties:

� Type of functional groups.

� Spatial arrangement of functional groups.

• Human body is an asymmetric environment.

� Proteins.� Proteins.

� Macromolecules.

• Better biological activity.

� Proper three-dimensional orientation.

� Very strong Drug-Receptor interaction.



Enantiomers

• Not superposable mirror-image isomers.

• The presence of a chiral center.

• Identical physicochemical properties.

• Differences:• Differences:

� Optical activity.

� Reaction with chiral molecules.

� Do they have different biological activities?



• (+)-Asparagine has a sweet taste.

• (–)-Asparagine has a bland taste.

• First reported by Piutti (1886).Associate Prof. Magdi A. Mohamed, Faculty


Three-point fit Hypothesis

• Selective reactivity of one enantiomer with its

receptor.

• Three-dimensional drug-receptor interaction.• Three-dimensional drug-receptor interaction.

• Easson and Stedman Hypothesis.



• The Easson-Stedman Hypothesis states that

the most potent enantiomer must be involved

in a minimum of three intermolecular

interactions with the receptor surface andinteractions with the receptor surface and

that the least potent enantiomer only

interacts with two sites.





A

D

C D

A

C

Hypothetical enantiomers



B B

A'

B'

C' A'

B'

C'

Hypothetical receptor

• The vasopressor response of N-

methyldopamine is the same as that of (S)-(+)-

adrenaline and less than that of (R)-(–)-

adrenaline.



• Two-point fit:

� N-Methyldopamine and (S)-(+)-adrenaline.

• Three-point fit:

� (R)-(–)-adrenaline.



• Differences in biological activity also can result

from differences in the ability of each

enantiomer to reach the receptor site.Associate Prof. Magdi A. Mohamed, Faculty


Diastereoisomers

• Nonmirror-image isomers.

� More than one chiral center.

� Double bonds.� Double bonds.

� Ring systems.

• Different physicochemical properties.

• Different biological activity.





Geometric Isomers



Hypothetical geometric isomers



Hypothetic receptor

Conformational Isomers

• Single bond rotation.

• Conformations (rotamers).• Conformations (rotamers).

• Interconvertable (bond rotation).









• Which conformation is favored?



• NMR, X-ray, and molecular orbital

calculations.calculations.

• Gauche conformer is favored.

• Intramolecular electrostatic interactions.

• Quaternary nitrogen and oxygen of the

carbonyl.



• Which conformation can properly

bind to cholinergic receptors?bind to cholinergic receptors?









• The (+)-trans-enantiomer was observed to be

equally as or more potent, than acetylcholine

at muscarinic receptors; it was much moreat muscarinic receptors; it was much more

potent than the (-)-trans-enantiomer.

• The racemic cis-compound had almost no

activity in the same muscarinic receptor test

system, and all compounds were very weak

nicotinic agonists.Associate Prof. Magdi A. Mohamed, Faculty


• Acetycholine would most probably interact

with muscarinic receptors in its less favored

anticlinal conformation (the angle between

the ester oxygen and the quaternary nitrogen

is 137°).Associate Prof. Magdi A. Mohamed, Faculty




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Physicochemical Principles of Drug Action