Receptor, Pharmacology

1. Receptors as Drug Targets
Capt. Htet Wai Moe
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2. INTRODUCTION
 Drugs produce their therapeutic effects
• by producing biochemical/ physical
changes in the target tissues
• of the host
• of the organisms which invade the host.
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3. These changes are due to;
 physical and chemical properties of
drug
 action on the drug targets namely;
Receptors
Enzymes
Carrier molecules
Ion channels
3

4. To get drug action, it is essential that-
1. Sufficient concentration of drug reaches
the site of action
2. Remains there for a sufficient duration
3. The tissue is susceptible for drug action
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5.  Magnitude of drug action is proportional to
the concentration of drug at the site of action.
 Receptor mechanism is very important to
understand the action and effect of a drug.
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6. Receptor
component of a cell or organism
interacts with a drug
initiates the chain of biochemical events
leading to the drug’s observed effects
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7. They have specific binding sites that are definite
in size and shape
Most are present on or near the membrane.
Some lie in the enzymes or genes
protein (polypeptide) in nature
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8. HISTORY OF RECEPTORS
Langley and Ehrlich introduced concept of
receptor
Langley (1852 – 1925);
• studied the effects of atropine against
pilocarpine induced salivation in cats
• postulated that there was a receptive substance
in the nerve ending or gland cell with which
both atropine and pilocarpine are capable of
forming compounds
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9. Ehrlich (1854 – 1915) observed that;
• certain dyestuffs acted selectively, staining some
cells more deeply or ina different way from other
cells
• suggested that drugs with selective actions on
particular cells could be developed
• Introduced the term “receptor”
9

10. Four major families of receptors;
ligand-gated ion channels (e.g. nicotinic ion
channel)
G-protein coupled receptors (e.g. α
adrenoceptor)
Enzyme linked receptors (e.g. insulin
receptors)
Nuclear receptors (e.g. glucocorticoid
receptors)
10

11. Receptors that do not fall into these four
receptor families;
Specific membrane ion pumps (e.g. Na+/K+
ATPase
Specific enzymes (e.g. 5-phosphodiesterase)
Structural proteins (e.g. colchicine to tubulin)
Cytosolic proteins< (e.g. ciclosporin to
immunophilins)
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12. Type-1
Ligand-gated
ion channels
Type-2
G-protein
coupled
receptor
Type-3
Enzyme-linked
receptor
Type-4
Nuclear
receptor
Location Membrane Membrane Membrane Intracellular
Effector Channel Channel or
Enzyme
Enzyme Gene
transcription
Coupling Direct G- protein Direct Via DNA
Examples Nicotinic
Receptor,
GABAA R
Muscarinic
receptor,
Adrenoceptors
Insulin receptor,
Growth factors,
Cytokine R
Steroid/
Thyroid
receptors
Time scale
for cellular
effects
Milliseconds Seconds Hours Hours/Days
Four main types of receptors
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13. Type (I) Ligand-gated ion channels
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.
13

14. control the fastest synaptic events in nervous
system
excitatory neurotransmitters such as Ach or
glutamate cause an increase in Na+ and K+
permeability
results in a net inward current
depolarizes the cell
generate an action potential
E.g. Nicotinic Receptor, GABA receptor, glycine
(inhibitory AA), excitatory AA-glutamate (kainate,
NMDA) and 5HT3 receptors
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15. Fig. Ion channel
Receptors
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16. Type(II) G-protein coupled receptors (GPCR)
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 and
Enabling to interact with a G-protein lied at the
inner leaf of the plasmalemma.
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17. G-protein
 G-protein consists of three subunits (α, β, and γ
subunits).
 In the inactive state, GDP is bound to α subunit.
 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
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18.  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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19. 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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20. one receptor can utilize more than one G-
protein (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
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21. Three major effector pathways of GPCRs
a) Adenylyl cyclase: cAMP pathway
activation of adenylyl cyclase results in
intracellular accumulation of second
messenger cAMP
cAMP functions mainly through cAMP-
dependent protein kinase
PK phosphorylates and alter the function of
many enzymes, ion channels, transporter,
transcription factors and structural proteins
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22. b) 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+
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23. Activated PKc
• phosphorylates many intracellular proteins
• mediates various physiological responses
Triggered by IP3, the released Ca2+ mediates
and modulates
• contraction,
• secretion/transmitter release,
• eicosanoid synthesis,
• neuronal excitability,
• membrane function, metabolism etc. 23

24. c) 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
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25.  Gs
• opens channel in myocardium and
skeletal muscles
 Gi and 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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26. Major functional pathways of G-protein coupled receptor
transduction

27. Diagrammatic representation of GPCR molecule

28. 28

29. Type(III) 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)
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30. The commonest protein kinases are receptor
tyrosine kinases (RTKs)
RTKs phosphorylates tyrosine residues on the
substrate proteins.
E.g. insulin, epidermal growth factor (EGF),
Nerve growth factor (NGF) and many other
growth factor receptors
30

31. Kinase - Linked receptor 31

32. Type(IV) Nuclear receptors
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.
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33. 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
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 33

34. This mRNA directs synthesis of specific proteins
which regulates activity of the target cells
E.g.corticosteroid, sex hormone and thyroid
hormone receptor stimulates transcription of
genes by binding to specific DNA consequences.
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35. 35
Fig. Operational scheme of intracellular (glucocorticoid) receptor

36. IMPORTANCE OF RECEPTOR CONCEPT
IN CLINICAL PRACTICE
1. Receptors largely determine the quantitative
relationship between concentration of drug
and pharmacologic effect
2. responsible for selectivity of drug action
3. mediate the action of agonists and antagonists
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37. Functions of receptors
1.Ligand binding
2.Message propagation(Signaling)
Functional domains within the receptor;
• ligand-binding domain
- spatially and energetically suitable for
binding the specific ligand
• effector domain
- which undergoes a functional
conformational change
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38. Receptor Effectors System
a receptor may be…….
 exerted directly on its cellular target(s),
effector proteins or
 conveyed by intermediary cellular
signaling molecules called transducers
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39. Signal transduction
Pathway from;
• ligand binding to conformational changes in the
receptor
• Receptor interaction with an effector molecule (if
present) and
• other downstream molecules called second
messengers
This cascade of receptor-mediated biochemical
events leads to a physiological effect
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40. Second messengers
 intracellular signaling molecules released by
the cell
 in response to exposure to extracellular
signaling molecules - the first messengers
 Second messengers initiates cellular signaling
through a specific biochemical pathway
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41. Second messengers (Contd)
 trigger a series of molecular interactions that
alter the physiologic state of the cell
 Well-studied second messengers
• cyclic AMP
• cyclic GMP
• cyclic ADP-ribose
• inositol phosphates
• Diacylglycerol
• nitric oxide, etc.
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42. 42
Receptor occupation theory
Most drugs bind to receptor by forming
• Hydrogen bond
• Ionic bond
• Van der Waals bond
These weak bonds are reversible.
In a few cases, drugs forms
• relatively permanent covalent bond

43. Affinity
• the tendency of drug to bind with the receptor
• to have affinity the chemical structure of the
drug and the receptor must be complementary
Efficacy (Intrinsic activity)
• the capacity of drug to induce a functional
change in the receptor

44. Potency
Potency of a drug depends on
• Affinity of receptors for binding the drug
• Amount of the drug(weight) in relation to its
effect
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45. A B R max
Response
Log concentration
Drug A is more potent than Drug B
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46. Maximal efficacy
The clinical effectiveness of a drug depends on
• its maximal efficacy
• its ability to reach the relevant receptors.
It is determined by
• mode of interaction of drug with receptors
(as partial agonists, antagonists, etc.) or
• characteristics of receptor–effectorsystem.
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47. A
B
Response
Log Concentration
Drug A is more efficacious than Drug B
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48. 48
Agonists
- have both receptor affinity and efficacy
There are three types of agonists;
1. Full agonists
2. Partial agonists
3. Inverse agonist

49. 49
Full agonists
- have affinity and maximal efficacy
Partial agonists
- have affinity and submaximal efficacy
Inverse agonists
- bind with the constitutively active receptors
and stabilize them
- reduce the activity (negative intrinsic activity)
- produce effect that are specifically opposite to
those of agonist

50. 50

51. Antagonists
• bind to the receptor but do not activate
generation of a signal.
• prevent the natural agonist fromexerting its
effects.
• only affinity, no intrinsic activity
Two types of Antagonist
Competitive antagonist or surmountable
antagonists.
Non-competitive or non-surmountable
antagonists. 51

52. Competitive or Surmountable
 effect can be overcome by more drug
(agonist).
The higher the concentration of antagonist
used, the more drug (agonist) you need to
get the same effect

53. 53

54. Non-competitive or Non-surmountable
 Antagonists that covalently bind to target
site
 The effect cannot be overcome by more
drug (agonist).
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55. 55

56. Spare receptors
Although the receptor occupation is
proportionate to drug concentration, not all the
receptors are occupied by the drug.
Some receptors called “spare receptors” remain
unaffected
said to be “spare” as maximal biologic response
is elicited without occupying full complement
of available receptors.
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57. Receptor Regulation
a) Receptor desensitization (Down-regulation)
 continuous stimulation with agonists generally
results in a state of desensitization
• adaptation
• refractoriness
• down-regulation)
 Effects to the same concentration of drug
diminished.
 This phenomenon, called tachyphylaxis
• occurs rapidly
• important therapeutically.
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58. Desensitization can result from;
 Temporary inaccessibility of the receptor to
agonist or
 Promote sequestration of receptor from the
membrane (internalization)
 Fewer receptors being synthesized and
available at the cell surface
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59. b) Supersensitivity/ Up-regulation
Supersensitivity to agonists follows chronic
reduction of receptor stimulation.
Following withdrawal from prolonged
receptor blockade (e.g. long-term
administration of β adrenergic receptor
antagonists)
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60. Supersensitivity can result from;
 unmasking of receptors
 synthesis and recruitment of new receptors
(up-regulation)
 accentuation of signal amplification by the
transducer
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61. 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 (2012)
3. Essentials of Medical Pharmacology by
KD Tripathi, 7th Edition (2013)
4. Pharmacology by George M. Brenner,
Craig W. Stevens, 4th Edition (2013)
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