various types of receptors, molecular structures and binding mechansim are discussed

1. RECEPTORS AS BIOLOGCAL
DRUG TARGETS
PRESENTED BY : UNDER THE GUIDANCE :
CH. ROHINI Dr. SHAHEEN BEGUM
2019MPH40B033 M.Pharm Ph.D.
M.PHARMACY 1st YEAR
PHARMACEUTICAL CHEMISTRY
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2. CONTENTS
 INTRODUCTION
 HISTORY
 DEFINITION OF RECEPTOR
 FUNCTIONS OF RECEPTORS
 NATURE OF RECEPTORS
 TYPES OF RECEPTORS
 BINDING AND ACTIVATION OF RECEPTORS
 AGONISTS VS ANTAGONISTS
 FORCES AFFECTING THE BINDING
 CONCLUSION
 REFERENCES
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3. INTRODUCTION
 Drugs produce their therapeutic effects by
producing biochemical or physical changes in the
target tissue of the host or of the organisms which
invade the host.
 These changes are due to :
- physical & chemical properties of drug
- action of drug on drug targets namely
1. Receptors
2. Enzymes
3. Carrier molecules
4. Ion channels
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4.  To get drug action, it is essential that :
1.Sufficient concentration of drug reaches the site
of action.
2.Remains there for sufficient duration.
3.The tissue is susceptible for drug action
 The largest number of drugs do not bind directly to
effectors.
 Eg : Enzymes , Structural proteins , Channels.
 But act through specific regulatory macromolecule (or) the
sites on them which bind and interact with the drug are
called Receptors.
 These are the sensing elements in the system of chemical
communication that co-ordinates functions of all the
different cells in the body.
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5. HISTORY OF RECEPTOR
 The birth of the receptor concept was the outcome of
circumstances in the lives of its two founding fathers.
 The immunologist and bacteriologist PAUL EHRLISH
(1854-1915).
 PAUL.EHRLICH designated the term RECEPTOR in
1900.
 The physiologist JHON NEWPORT LANGLEY (1852-
1925),known as father of chemical receptor theory.
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6. DEFINITION OF RECEPTOR
 It is defined as a protein macromolecule (or)
binding site located on the surface (or) inside the
effector cell that serves to receive a chemical
signal .
(or)
They can referred to as cylindrical
macromolecules which offers site towards drug to
bind to them ultimately show their effect on the
cell.
These are highly specific.
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7.  Chemical signals are released by signaling cells in the
form of small, usually volatile or soluble molecules called
ligands.
Forms of chemical signaling
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8. FUNCTIONS OF RECEPTORS
 Amplify the signals.
 Mainly two functions 1.ligand binding
2.Message propagation
 To integrate various extracellular and intracellular
regulatory signals.
 Every receptor has contain two domains
 ligand binding domain
 Effective domain
 LIGAND BINDING DOMAIN :
 It is the site where the binding of the agonist of the
drug is done.
 EFFECTIVE DOMAIN :
 After binding of the receptor changes is occurs that is
called effective domain.
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9. 9

10. NATURE OF RECEPTORS
 Receptors are regulatory macromolecules ,
mostly proteins.
 Majority of receptors molecule are made up of
several non- identical sub units.
 Most of receptors are lipoproteins are often
firmly embedded in the plasma membrane as
intrinsic proteins.
 Most of the drugs receptors are coupled to
adenylyl cyclase, the enzyme responsible for the
formation of cAMP.
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11. TYPES OF RECEPTORS
 There are 2 types of receptors. Those are :
 INTERNAL / INTRACELLULAR / CYTOPLASMIC
RECEPTORS
 CELL SURFACE RECEPTOR.
1. LIGAND GATED ION CHANNELS
2. G - PROTEIN COUPLED RECEPTORS
3. RECEPTOR TYROSINE KINASES
 NUCLEAR RECEPTORS
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12. INTERNAL RECEPTOR
 Found in the cytoplasm of the cell.
 Respond to hydrophobic ligand molecules.
 Hydrophobic signaling molecules typically diffuse
across the plasma membrane.
 Interact with intracellular receptors in the cytoplasm.
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13. CELL SURFACE RECEPTOR
 Membrane anchored proteins that bind to ligands on the
outside surface of the cell.
 Performs signal transduction.
 Converting an extracellular signal into an intracellular
signal.
 3 MAIN COMPONENTS :
i. an external ligand - binding domain (extracellular
domain),
ii. a hydrophobic membrane-spanning region,
iii. an intracellular domain inside the cell.
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14. 14

15. LIGAND GATED ION
CHANNELS
 Also called ionotropic receptors, coupled directly to
membrane ion channels.
 Agonist binding
• opens the channel.
• causes depolarization / hyperpolarization / changes in
cytosolic ionic composition.
• depending on the ion that flows through.
 Control the fastest synaptic events in nervous
system.
 Excitatory neurotransmitters such as Ach or
glutamate cause an increase in Na+ and K+
permeability.
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16.  results in a net inward current
 depolarizes the cell
 generate an action potential
 E.g. Nicotinic Receptor, GABA receptor, 5HT3 receptors.
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17. ION CHANNEL MECHANISM
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18. G - PROTEIN COUPLED
RECEPTORS
 Metabotropic or Seven α-helical membrane spanning
hydrophobic amino acid segments.
 Run into 3 extracellular and 3 intracellular loops
 Binding of the mediator molecule induces a change in the
conformation.
 Enabling to interact with a G-protein lied at the inner leaf
of the plasmalemma.
G-PROTEIN :
 G-protein consists of three subunits (α, β, and γ subunits).
 In the inactive state, GDP is bound to α subunit.
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19.  Activation leads to displacement of GDP by GTP.
 Activated Gα-GTP dissociates from β, and γ subunits,
then associates with an effector protein, and alters its
functional state.
 The α-subunit slowly hydrolyzes bound GTP to GDP.
 Gα-GDP rejoin the β and γ subunits.
 The βγ dimer can activate receptor-operated K+ channels,
inhibit voltage gated Ca2+ channels and promote GPCR
desensitization at higher rates of activation.
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20.  The important G proteins with their action on the effector;
 Gs : Adenylyl cyclase activation, Ca2+ channel
opening.
 Gi : Adenylyl cyclase inhibition, K+ channel opening.
 Go : Ca2+ channel inhibition.
 Gq : Phospholipase C activation.
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21.  one receptor can utilize more than one Gprotein (agonist
pleiotrophy), e.g.
RECEPTOR COUPLER
 Muscarinic M2 Gi, Go
 Muscarinic M1,M3 Gq
 Dopamine D2 Gi, Go
 β-adrenergic Gs
 α1-adrenergic Gq
 α2-adrenergic Gi, Go
 Three major effector pathways of GPCR’S :
1. ADENYLYL CYCLASE : cAMP PATHWAY
2. PHOSPHOLIPASE C : IP3-DAG PATHWAY
3. CHANNEL REGULATION.
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22. 1. ADENYLYL CYCLASE : cAMP PATHWAY
 Activation of adenylyl cyclase results in intracellular
accumulation of second messenger cAMP.
 cAMP functions mainly through cAMPdependent
protein kinase (PK).
 PK phosphorylates and alter the function of many
enzymes, ion channels, transporter, transcription factors
and structural proteins.
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23. ADENYLYL CYCLASE PATHWAY
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24. 2. PHOSPHOLIPASE C : IP3-DAG PATHWAY
 Activation of phospholipase C hydrolyses membrane PIP2
to generate the second messengers IP3 and DAG.
 INOSITOL TRISPHOSPHATE (IP3) :
• diffuses to cytosol
• mobilizes Ca2+ from endoplasmic reticular depots
 DIACYLGLYCEROL (DAG) :
• remains within the membrane
• recruits protein kinase C (PKc)
• activates it with the help of Ca2+.
 ACTIVATED PKc :
• phosphorylates many intracellular proteins
• mediates various physiological responses
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25.  Triggered by IP3, the released Ca2+ mediates and
modulates :
• Contraction,
• Secretion/transmitter release,
• Eicosanoid synthesis,
• Neuronal excitability,
• Membrane function, metabolism etc.
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26. PHOSPHOLIPASE C / IP3 / DAG
PATHWAY
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27. 3. CHANNEL REGULATION
 The activated G-proteins (Gs, Gi, Go)
• can open or inhibit ionic channels specific for Ca2+
and K+
• without the intervention of any second messenger like
cAMP or IP3
 hyperpolarization/ depolarization/ changes in intracellular
Ca2+ can occur.
Gs :
 opens channel in myocardium and skeletal muscles.
Gi & Go :
 opens K1+ channels in heart and smooth muscle
 inhibit neuronal Ca2+ channels
 Direct channel regulation is mostly the function of βγ
dimer.
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28. CHANNEL REGULATION
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29. 29

30. Overview of GPCR
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31. 31

32. ENZYME LINKED RECEPTORS
 lie partially outside and partially inside the cell membrane.
 consist of extracellular ligand binding domain linked to
intracellular domain by single transmembrane helix.
 Intracellular portion is enzyme in nature. (protein kinase
generally and guanylyl cyclase in some cases).
 The commonest protein kinases are receptor tyrosine
kinases (RTKs)
 RTKs phosphorylates tyrosine residues on the substrate
proteins.
 Eg. insulin, epidermal growth factor (EGF), Nerve growth
factor (NGF) and many other growth factor receptors
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33.  Important pathways activated :
1. The Ras/Raf/mitogen- activated protein (MAP) kinase
pathway
- activated by tyrosine kinases.
- important in cell division, growth, differentiation.
2. The Jak/Stat pathway
- activated by cytokines.
-controls synthesis and release of inflammatory
mediators.
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34. KINASE RECEPTOR PATHWAY
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35. KINASE LINKED RECEPTOR
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36. NUCLEAR RECEPTOR
 Intracellular (cytoplasmic or nuclear) soluble proteins
which respond to lipid soluble chemical messengers that
penetrate the cell.
 When the hormone binds to the receptor protein :
• The receptor dimerizes.
• The DNA binding regulatory segment folds into the
requisite configuration.
 This dimer :
• Moves to the nucleus.
• Binds other co-activator/ co-repressor proteins which
have a modulatory influence on its capacity to alter gene
function.
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37.  The whole complex
• attaches to specific DNA sequences of the target genes
• facilitates or repress their expression
• specific mRNA is synthesized/repressed on the
template of gene.
 This mRNA directs synthesis of specific proteins which
regulates activity of the target cells.
 Eg. corticosteroid, sex hormone and thyroid hormone
receptor stimulates transcription of genes by binding to
specific DNA consequences.
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38. 38

39. Operational scheme of intracellular
(Glucocorticoid) receptor
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40. OVERVIEW OF RECEPTORS
40

41. BINDING AND ACTIVATION OF
RECEPTORS
 Binding of a ligand to a receptor :
- Changes its shape or activity
- Allowing it to transmit a signal or directly produce a
change inside of the cell.
 LIGAND – is the molecule that binds to another specific
molecule.
 Specific ligand will have a specific receptor that typically
binds only that ligand.
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42.  BINDING AFFECTS DRUG ACTION :
 Drugs produce effects by interacting with special
macromolecular components(receptor) forming drug-
receptor complex & modify the function of the receptor.
 Drug+Receptor -> Drug-receptor complex ->
Modified biological function
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43. AGONISTS VS ANTAGONISTS
 CLASSIFICATION OF LIGANDS :
 Ligands are classified by effect upon binding to the
receptor.
 LIGANDS :
1. Agonist
2. Antagonist
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44.  AGONIST : A drug that binds to physiological
receptor and mimic the regulatory effects of
endogenous substance.
 PROPERTIES OF AGONIST :
- Acute Signaling
- Desensitization
- Sequestration
- Resensitization.
 Receptors can be activated either by endogenous or
exogenous , leads to change in the biological response.
 Types of agonists :
a) Full agonist
b) Partial agonist
c) Inverse agonist
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45. AGONIST BINDING TO DIFFERENT
RECEPTORS
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46.  FULLAGONIST – The ligands that increase the activity
of the receptors & produce the maximal response .
 Ex.- Morphine ,mimics the action of endorphins at opioid
receptors.
 PARTIALAGONIST – These ligands partially increase
the activity of the receptors but do not produce the maximal
response like full agonist even when present in excess
amount.
 Ex.- Buspirone , is an anxiolytic drugs , used to treat an
anxiety disorder.
 INVERSE AGONIST – The ligands which decrease the
activity of an active receptors to their inactive state.
 Ex.- Flumazenil drugs acts as a inverse agonist for the
GABA receptor & produce anxiogenic effect.
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47.  ANTAGONIST : when it binds to a receptor and
prevents (blocks or inhibits) a natural compound or a
drug to have an effect on the receptor.
 PROPERTIES OF ANTAGONIST :
- Site selectivity.
- Structural conformation – mimics with the natural
ligand.
- Reduces the response.
- Effect may be temporary or permanent.
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48.  TYPES OF ANTAGONISTS :
1. Reversible
- Non-competitive
- Competitive
2. Irreversible
1. REVERSIBLE ANTAGONISTS :
 NON-COMPETITIVE ANTAGONISTS :
The antagonist binds at a different site other than
orthosteric site on the receptor.
 The effect of the antagonist cannot be overcome by
increasing the concentration of agonist.
 Ex.- Binding of cyclothiazide with mGLUR1 receptor.
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49. COMPETITIVE /SURMOUNTABLE ANTAGONISTS :
 The antagonist competes with the agonist for the
orthosteric site of the same receptor.
 The effect of the antagonist can be overcome by increasing
the concentration of agonist.
 Eg : IL-1RA protein competes with the cell surface
interluekins.
Competitive antagonist Non competitive antagonist
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50.  IRREVERSIBLE ANTAGONISTS :
 May or may not competes with the agonist for orthosteric
sites for binding to the receptor.
 Forms covalent bond to the site.
 Ex.- Aspirin.
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51. 51

52. REPRESENTATION OF AGONIST & ANTAGONIST
MECHANISMS
52

53. FORCES AFFECTING THE BINDING
 3 major types of chemical forces/bonds. Those are :
1. Covalent bond
2. Electrostatic bond
3. Hydrophobic interaction.
 1. COVALENT BOND :
• very strong
• "irreversible" under biological conditions.
• extremely stable.
 Example : It is formed between the activated form of
Phenoxybenzamine and the α-adrenergic-receptor.
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54.  2. ELECTROSTATIC BOND :
• Very common & weaker than covalent.
• Interaction strength is variable
 Example : van-der Waals forces.
 3. HYDROPHOBIC INTERACTIONS :
• Generally weak, but important.
• Significant in driving interactions.
• Lipophilic drugs and the lipid component of
biological membranes.
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55. CONCLUSION
 Receptors are the molecules which are essential for
majority of biochemical and metabolic processes in the
body.
 Extensive research is being done on the pharmacology to
find out new class of receptors.
 Discovery about mechanism of orphan receptors can lead
to drug development for the effective treatment of
diseases.
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56. REFERENCES
 1. Basic and clinical pharmacology by Bertram G. Katzung, 12th
edition (2012)
 2. Pharmacology by H. P. Rang, M.M. Dale, J.M. RITTER, 7th Edition
 3. Essentials of Medical Pharmacology by KD Tripathi, 7th Edition .
 4. Pharmacology by George M. Brenner, Craig W. Stevens, 4th Edition
 The cell (5th Edition) Cooper & Hausman
 Lehninger principle of biochemistry (5th Edition)
 Handbook of cell signaling Vol.1 (2nd Edition)
 A Presentation on “Receptor regulation and receptor related diseases”
by “Dr. Plessan Joy”
 https://en.wikipedia.org/wiki/Receptor_(biochemistry).
 Wilson and Gisvold”s Textbook of Organic medicinal and
pharmaceutical chemistry (Twelth edition) by John M.Beale,jr. John H.
Block.
 Textbook of medicinal chemistry (synthetic & Biochemical Approach)
vol – І by prof. Surendra Nath Pandeya.
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