ms-drugreceptor-assg-1

8/2/2019 MS-DrugReceptor-Assg-1

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INTERACTION

OF DRUG AND

RECEPTOR &

ITS THEORY

MEDICINAL

CHEMISTRY

Semister # 2- 2012


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Contents

INTRODUCTION

INTERACTION INVOLVED IN THEDRUG-RECEPTOR COMPLEX

THEORIES OF DRUG-RECEPTOR INTERACTION

REFERENCES


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INTRODUCTION

1878 Langley

Study of antagonistic action of alkaloids on cat salivary flow suggests the compounds interacted

with some substance in the nerve endings

1897 Ehrlich

Side chain theory - Cells have side chains that contain groups that bind to toxins - termed receptors

1906 Langley

Studying antagonistic effects of curare on nicotine stimulation of skeletal muscle Concluded receptive substance

that received stimulus, and by transmitting it, caused muscle contraction

Two fundamental characteristics of a receptor:

1. Recognition capacity - binding2. Amplification - initiation of response

Binding produces a conformational change

Conformational change translated into functional change in protein (Stimulus)

Ionic conductance

Binding/release of G-proteins

Change in conductance/enzymatic activity translated into physiologic changes (response)

Agonistactivates (turns on) receptor. Can be full or partial.

Antagonist blocks response of an agonist.

i d i ( ff) i i l i


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Table 3.1Neurotransmitter

NH2

Agonists

HN N

NH2

CH3O

Antagonists

N

N

N(C H3)2

HN N CH3Pyrilamine

Agonists - often

structural similarity

Antagonists - little

structural similarity

Histamine NH2N

OH

Cl

MeO

N N CH3

Chlorcyclizine

ON N N

OH HOHO

NHCH3HO

Epinephrine

NHCH3 MeO

ON

NH2

Prazosin


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How can agonists and antagonists bind to same site and one show

response,

other not?

Figure 3.14

A B C

Agonist antagonist enantiomer


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How can drugs play a role? Consider problematic states:Too many chemical messengers released

A drug could be developed to block receptors (antagonist)

Too few chemical messengers released

A drug could serve as a replacement messenger (agonist)

Design of Agonist

Requires knowledge of the endogenous messenger requirements:

correct binding groups correct position of binding groups correct size for binding site similarity to structure of endogenous messenger

Binding Groups

Similar characteristics to endogenous substrate

H-bonds vdw forces ionic


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Size and Shape

Binding Groups and Framework may be ok but other groups on the drug may prevent drug from binding(i.e., cant get close enough)


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Forces Involved in a Drug-Receptor Complex

Covalent Bonds

Ionic Interactions

Ion-Dipole & Dipole-Dipole Interactions

Hydrogen Bonds

Charge-Transfer Complexes

Hydrophobic Interactions

Van der Waals Forces

Covalent Bonds

Extremely strong bonds (-40 to -110 kcal/mol)

Less common for drug-receptor complexes (except for labeling experiments)

More common for enzyme or DNA interactions with drugs.

Ionic Interactions (at physiological pH; 7.4)

Mutual attraction of opposite charges

Basic groups such as amines (from arginine, lysine, and histidine)

Acidic groups such as carboxylic, phosphoric, sulfonic acids (glutamic and aspartic acid) ~ -5 kcal/mole (depends upon magnitude of charge and distance) and may be enhanced by additional

interactions.


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-1 to -7 kcal/mol

Hydrogen Bonds

Dipole-dipole interactions involving X-H groups (X is electronegative) and other electronegative groups (Y).

Y = N, O, F

May be intramolecular or intermolecular

~ -3 to -5 kcal/mol


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Electron acceptors contain electron-deficient-orbitals (alkenes, alkynes, and aromatic groups with

electron-withdrawing substituents, or weakly acidic protons). In a receptor, Donors = tyrosine (aromatic) or carboxylates (asparate orglutamate).

In a receptor, Acceptors = cysteine,

Acceptor & Donor = histidine, tryptophan, asparagine

~ -1 to -7 kcal/mol

Example: may be involved in the intercalation of planar antimalarial drugs such as chloroquinone intoparasitic DNA (see figure below)

Hydrophobic Interactions

Hydrophobic groups cause water molecules to orient themselves around them.

Therefore, there is higher order or energy in such cases.

When two hydrophobic groups approach each other, the highly ordered watermolecules become less ordered

and the Increase of entropy results in a decrease of free energy. This decrease in free energy is the hydrophobic interaction.

Therefore, not an attractive force.


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Van der Waals Forces

Temporary dipoles from drug or receptor induce opposite dipoles in the approaching molecule.

Significant with close surface contact of atoms from each source.

More significant in the cases of molecular complementarity

~ -0.5 kcal/mol each atomic interaction


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THEORIES OF DRUG-RECEPTOR INTERACTION

Occupancy Theory (1926)

Intensity of pharmacological effect is

directly proportional to number of receptorsoccupied

Does not rationalize how two drugs can occupy the same

receptor and act differently


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Drug-Receptor Theories

Occupancy Theory (1926)

Intensity of pharmacological effect is directly

proportional to number of receptors occupied

Does not rationalize how two drugs can occupy

the same receptor and act differently


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Rate Theory (1961)

Activation of receptors is proportional to thetotal number of encounters of a drug with its

receptor per unit time.

Does not rationalize why different types ofcompounds exhibit the characteristics they do.

kondrug + receptor drug-receptor complex

koff

[drug][receptor]Kd =

[drug-receptor complex]


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Induced Fit Theory (1958) Agonist induces conformational change - response

Antagonist does not induce conformational change - noresponse

Partial agonist induces partial conformational change -partial response

Figure 3.16


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Activation-Aggregation TheoryMonad, Wyman, Changeux (1965) Karlin (1967)

Receptor is always in a state of dynamic equilibrium

between activated form (Ro) and inactive form (To).

Ro Tobiologicalresponse

no biologicalresponse

Agonists shift equilibrium to Ro

Antagonists shift equilibrium to To

Partial agonists bind to both Ro and To

Binding sites in Ro and To may be different, accounting

for structural differences in agonists vs. antagonists


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Two-state (Multi-state) Receptor ModelR and R* are in equilibrium D D

(equilibrium constantL), which + +defines the basal activity of the Lreceptor. R R*

Full agonists bind only to R*

Partial agonists bind preferentiallyto R*

Full inverse agonists bind only to R

resting

Kd

D R Figure 3.17

active

Kd*

D R*

Partial inverse agonists bind preferentially to R

Antagonists have equal affinities for both R and R* (no effect on

basal activity)

In the multi-state model there is more than one R state to account


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for variable agonist and inverse agonist behavior for the same

receptor type.


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Drug and Receptor ChiralityDrug-Receptor Complexes

Receptors are chiral (allL-amino acids)

Racemic mixture forms two diastereomeric

complexes[Drug]R + [Drug]S + [Receptor]S

[Drug]R [Receptor]S + [Drug]S [Receptor]S

Have different energies and stabilities


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Receptor InteractionH H

OH

HO CH2NH2CH3+

HO CH2NH2CH3

HOOH

Ar -

+HO

Ar -

R-(-)-epinephrine S-(+)-epinephrineFigure 3.20

Ligand enantiomers cannot be distinguished

with only two points of attachment.


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Three-point attachment conceptH

HO CH2NH2CH3+

HOH

HO CH2NH2CH3

HOOH

HO+

Ar -

H

Ar -

H

R-(-)-epinephrine S-(+)-epinephrineFigure 3.21

Receptor needs at least three points of attachment

to distinguish enantiomers of a ligand.


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References:

1. The Organic Chemistry of Drug Design and Drug Action by Richard B. Silverman Ph.D Organic Chemistry, 2nd Edition,Chapter 3 Receptors.

2. Principles of Organic Medicinal Chemistry by Rama Nao Nadendla.3. Foye's Principles of Medicinal Chemistry byDavid A. Williams,William O. Foye,Thomas L. Lemke4. An Introduction to Medicinal Chemistry by GRAHAM L. PATRICK. OXFORD UNIVERSITY.
http://www.amazon.com/s/ref=ntt_athr_dp_sr_1?_encoding=UTF8&sort=relevancerank&search-alias=books&ie=UTF8&field-author=Richard%20B.%20Silverman%20Ph.D%20Organic%20Chemistryhttp://www.amazon.com/s/ref=ntt_athr_dp_sr_1?_encoding=UTF8&sort=relevancerank&search-alias=books&ie=UTF8&field-author=Richard%20B.%20Silverman%20Ph.D%20Organic%20Chemistryhttp://www.google.com.pk/search?tbo=p&tbm=bks&q=inauthor:%22David+A.+Williams%22http://www.google.com.pk/search?tbo=p&tbm=bks&q=inauthor:%22David+A.+Williams%22http://www.google.com.pk/search?tbo=p&tbm=bks&q=inauthor:%22David+A.+Williams%22http://www.google.com.pk/search?tbo=p&tbm=bks&q=inauthor:%22William+O.+Foye%22http://www.google.com.pk/search?tbo=p&tbm=bks&q=inauthor:%22William+O.+Foye%22http://www.google.com.pk/search?tbo=p&tbm=bks&q=inauthor:%22William+O.+Foye%22http://www.google.com.pk/search?tbo=p&tbm=bks&q=inauthor:%22Thomas+L.+Lemke%22http://www.google.com.pk/search?tbo=p&tbm=bks&q=inauthor:%22Thomas+L.+Lemke%22http://www.google.com.pk/search?tbo=p&tbm=bks&q=inauthor:%22Thomas+L.+Lemke%22http://www.google.com.pk/search?tbo=p&tbm=bks&q=inauthor:%22Thomas+L.+Lemke%22http://www.google.com.pk/search?tbo=p&tbm=bks&q=inauthor:%22William+O.+Foye%22http://www.google.com.pk/search?tbo=p&tbm=bks&q=inauthor:%22David+A.+Williams%22http://www.amazon.com/s/ref=ntt_athr_dp_sr_1?_encoding=UTF8&sort=relevancerank&search-alias=books&ie=UTF8&field-author=Richard%20B.%20Silverman%20Ph.D%20Organic%20Chemistry

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