1. RECEPTORS AND RECEPTOR
SUPERFAMILIES
Dr.Rahul Kunkulol
Asso. Professor dept. of Pharmacology
RMC,LONI

2. INTRODUCTION
“Corpora non agunt nisi fixate”.
P. Ehrlich (1908)
Paul Ehrlich described drug-receptor
binding:
(“Agents do not act unless they are bound”)

3. Drugs
Drugs can be defined as agents
that uniquely interact with
specific target molecules in the
body, thereby producing a
biological effect.

4. Drugs can be
stimulatory or
inhibitory

5. Drugs
Drugs interact with biological systems in ways that
mimic, resemble or otherwise affect the natural
chemicals of the body.
• - or -
Drugs can produce effects by virtue of :
• Acidic or basic properties (e.g. Antacids, protamine)
• Surfactant properties (amphotericin)
• Ability to denature proteins (astringents)
• Osmotic properties (laxatives, diuretics)
• Physicochemical interactions with membrane lipids (general and
local anesthetics).

6. DRUG SPECIFICITY
Specificity is reciprocal:
Individual classes of drug bind only to certain
targets, and individual targets recognized only
certain classes of drug.
No drugs are completely specific in their action.
In many cases increasing the dose of a drug will
cause it affect target other than the principle
one, and this can lead to side effects. E.g. TCA

7. Targets for drug action
•Receptor
•Ion channels
•Enzymes
•Carrier molecules
Four kinds
of regulatory
protein
involved as
primary drug
targets.

8. Targets for drug action

9. ION CHANNELS
Ligand gated ion channels –incorporate a
receptor and open or close only when the
receptor is occupied by an agonist. Ex.-
Local anesthetics (direct)
Voltage gated ion channels-drugs binds on
accessory sites on the channel protein and
affect channel gating.Ex.- dihydropyridines
(indirect)

10. ENZYMES
Many drugs target enzymes.
Often the drug molecule is a substrate
analogue that act as a competitive inhibitor of
the enzyme ,either reversibly or irreversibly.
Examples:-
Enzymes Inhibitors
Acetylcholinesterase Neostigmine
Cyclooxygenase Aspirin

11. CARRIER MOLECULE
 The transport across cell membranes of ions and
organic molecules generally requires a carrier
protein .
Ex.
1.Transport of glucose,a.a. into the cell.
2.Transport of ions, organic molecule into the
tubule.

12. RECEPTOR
 Receptor are the sensing elements in the system of
chemical communications that coordinates the function
of all the different cells in the body.
 Chemical messengers :
Hormones
Drugs
Transmitters
Other mediators

13. Drug and receptor
Drugs, as well as hormones,
neurotransmitter, autacoids and toxins can
make possible the transfer of information
to cells by interaction with specific
receptive molecules called “receptors”.
Receptor
DRUG

14. DRUG RECEPTOR
INTERACTION
Occupation of receptor by a drug molecule may or may not
result in activation of the receptor.

15. Drug-Receptor Interactions
Drug-receptor interactions serve as signals to trigger a cascade of
events. This cascade or signaling pathway, is a collection of many
cellular responses which serve to amplify the signal and produce a final
effect.
Effectors are thus the molecules that translate the drug-receptor
interaction into changes in cellular activity.
   +          EFFECT
DRUG DRUG + RECEPTOR DRUG + RECEPTOR EFFECTOR EFFECTOR
INTERACTION COMPLEX SYSTEM
STIMULUS BINDING ACTIVATION TRANSDUCTION AMPLIFICATION RESPONSE
SIGNALLING PATHWAY

16. Classification of Receptors
IUPHAR (International Union of Pharmacological Science)
Pharmacological
Mediator (i.e. Insulin, Norepinephrine, estrogen)
Biochemical and Biophysical
Second messenger system (i,.e. cAMP, PLC, PLA)
Molecular or Structural
Subunit composition (i.e. 5HT1A )
Anatomical
Tissue (i.e muscle vs ganglionic nAChRs)
Cellular (i.e. Membrane bound vs Intracellular)

17. RECEPTOR SUPERFAMILIES
 LIGAND- GATED ION CHANNELS
 G-PROTEIN COUPLED RECEPTORS
 KINASE LINKED RECEPTORS
 NUCLEAR RECEPTORS

18.  Type- Ionotropic receptors
 Location-cell membrane
 Effector-ion channel
 Coupling-direct
 Examples-Fast neurotransmitters :
 Nicotinic Ach
 Glutamate
 GABAA,
LIGAND GATED ION
CHANNELS

19. LIGAND GATED ION CHANNELS

20. GATING MECHANISM
Neurotransmitter
Post synaptic membrane inotropic receptor (LGIC)
Increased permeability of ions
Depolarization
Action potential

21. STRUCTURE OF ACH NICOTINIC
RECEPTOR

22. GABAA RECEPTOR

23. GABAA RECEPTOR

24. GABA
metabolites
Succinic
Semialdehyde
GT: GABA transaminase SSD: Succinic semialdehyde dehydrogenase
GT
SSD
Cl-

25. G – PROTEIN COUPLED
RECEPTORS
 Type: Metabotropic
 Location: Cell membrane
 Coupling: G-protein
 Exampels-
 Muscarinic, Adrenergic,
 Opioid, Dopamine,
 5HT,Peptides,Purines

27. SIGNAL TRANSDUCTION

28. CLASSES OF G-PROTEINS
 Gs
 Gi
 Gq
 Go
Amplification………..?

30. Receptor Signaling Pathways
Adenylate Cyclase (AC)
Guadenylyl Cyclase (GC)
Phospholipase C (PLC)
Phospholipase A (PLA2)
Nitric oxide Synthase
Ions
 cAMP
 cGMP
 DAG and IP3
 Arachidonic acid
 NO and CO
 Na+
, Ca2+
, K+
, Cl-

31. Adenylate Cyclase
 ATP cAMP Activation of PK
Phosphorylation of
cell proteins
5AMP
Enzymes involved in energy metabolism, cell division, cell differentiation,
ion channels, and contractile proteins in smooth muscles

32. REGULATION OF ENERGY BY
CAMP

33. PHOSPHOLIPASE C

34. ION CHANNELLS AS TARGET
FOR G- PROTEINS
 GPCR controls ion channels directly by
mechanism that they do not involve second
messengers like cAMP or IP3.
 Either alpha or beta and gamma subunits of G
protein acts as second messenger
 Ex-m ACH receptor enhances K+ permeability

35. KINASE LINKED RECEPTORS
 Mediate the actions of wide variety of proteins
mediators including growth factors, cytokines &
hormones such as insulin.
 Receptor for various hormones (insulin) & growth
factor incorporate tyrosine kinase activity in their
intracellular domain.
 Cytokine receptors have intracellular domain that
activates cytosolic kinases when the receptor is
occupied.

36. SIGNAL TRANSDUCTION
Receptor
Ligand binding
Dimerisation of receptor
Autophosporylation of tyrosine residue
Binding of intracellular proteins
Gene transcription

38. NUCLEAR RECEPTORS
 Nuclear receptors regulate gene transcription.
 Nuclear receptor-a misnomer as they are located
in the cytosol and migrate to nucleus when
ligand is present.
 Examples: Steroid hormones, thyroid hormones
retinoic acid and vit. D.

39. Steroid
Receptor
Confomational change
Dimer
Move to nucleus and bind to hormone – responsive elements
Increase RNA Polymerase activity
Production of specific m RNA

40. NUCLEAR RECEPTORS

41. RECEPTOR SUPERFAMILIES

42. RECEPTOR SUPERFAMILIES

43. DESENSITISATION &
TACHYPHYLAXIS
Definition:
 TACHYPHYLAXIS
The effect of a drug gradually diminishes when it is given
continuously or repeatedly, which often develops in the
course of minutes.
 Tolerance is conventionally used to describe a more gradual
decrease in responsiveness to a drug, taking days or weeks to
develop.
The distinction is not sharp.
 Refractoriness is used to indicate loss of therapeutic efficacy.
 Drug resistance is used to indicate loss of effectiveness of
antimicrobial or anti tumor drugs.

44. MECHANISMS
 Loss or change in receptors
 Exhaustion of mediators
  metabolic degradation
 Physiological adaptation
 Active extrusion of drug from cell

45. Drug-Receptor Interactions
Theory and assumptions of drug-receptor interactions.
 Drug Receptor interaction follows simple Law mass-action
relationships,
 The magnitude of the response is proportional to the fraction of
total receptor sites occupied by drug molecules.
 Combination or binding to receptor causes some event which
leads to a response.
 Response to a drug is graded or dose-dependent.

47. Agonism and Antagonism

48. Cont..
AGONIST: Binding + Activation
Agonists facilitate receptor response
ANTAGONIST: If a drug binds to the receptor without
causing activation and thereby prevents the agonists from
binding, is termed as Antagonist.
Tendency of a drug to bind the receptor is governed by its
affinity, where as tendency of it, ones bound, to activate
the receptor is denoted by its efficacy.
PARTIAL AGONISTS: Drugs with intermediate levels of
efficacy, such that even if 100% of receptors are occupied
the tissue response is sub maximal.

49. PARTIAL & FULL AGONIST

50. Partial Agonists
 Full agonists  max
response
 Full response @ ~20%
occupancy
 Partial agonists 
sub maximal
response
 100% occupancy 
~40% response

51. Comparison of Affinity & Efficacy of
Ligands
Ligand Affinity Efficacy
Agonist ++++ ++++
Antagonist ++++ -
Partial agonist ++++ ++

52. TWO STATE MODEL
 The receptor shows the two conformational
stage resting (R) and activated (R*) which exist
in equilibrium.
 R R*
 Normally when no ligand is present, the
equilibrium lies far to the left.

53. In the presence of ligand (A) equilibrium will
depend on equilibrium constant i.e. /.
 For pure antagonist it is zero.
 For agonist it is a finite value.
 For drug X / is small – partial agonist
 For drug Y / is large – agonist
 Therefore constant / is measure of efficacy

54. R+D=

55. DRUG ANTAGONISM
 The effect of one drug is diminished or completely
abolished in the presence of another.
CLASSIFICATION
 Chemical antagonism
 Pharmacokinetic antagonism
 Antagonism by receptor block
 Noncompetitive antagonism, i.e. block of receptor –
effector linkage
 Physiological antagonism

56. Cont…
CHEMICAL ANTAGONISM
 Two substances combine in solution and effect of active drug is
lost, e.g. Dimercaprol bind to heavy metals
PHARMACOKINETIC ANTAGONISM
 In this antagonist effectively reduces the concentration of the
active drug at its site of action. This can happen various ways by
increased metabolic degradation, decreased absorption or
increased excretion.

57. REVERSIBLE COMPETITIVE ANTAGONISM
•Antagonist binds receptor but does not activates it.
•Incr’d [agonist] restores tissue response to agonist
•Antagonism “surmountable
•In the presence of antagonist, the agonist log
concentration effect curve is sifted to the right
without change in slope or maximum.

58. Antagonism-Competitive

59. IRREVERSIBLE COMPETITIVE ANTAGONISM
•In this antagonist dissociates very slowly or not at
all resulting in no change in antagonist occupancy
when agonist is applied.
Covalently bind receptors
 Irreversible, insurmountable antagonism
↓ number of available receptors -- ↓ agonist max
response

60. IRREVERSIBLE COMPETITIVE ANTAGONISM

61. NONCOMPETITIVE ANTAGONISM
 Antagonists blocks at some points chain of events that
lead to production of response by agonist.
 Effect will be slope and maximum of the agonist log
concentration response curve.
PHYSIOLOGICAL ANTAGONISM
 In this there is interaction of two drugs whose
opposing action in the body tend to cancel each other
example – Histamine and Omeprazole on parietal cell
of gastric mucosa.