RECEPTORS AND RECEPTOR
SUPERFAMILIES
Dr.Rahul Kunkulol
Asso. Professor dept. of Pharmacology
RMC,LONI
INTRODUCTION
“Corpora non agunt nisi fixate”.
P. Ehrlich (1908)
Paul Ehrlich described drug-receptor
binding:
(“Agents do ...
Drugs
Drugs can be defined as agents
that uniquely interact with
specific target molecules in the
body, thereby producing ...
Drugs can be
stimulatory or
inhibitory
Drugs
Drugs interact with biological systems in ways that
mimic, resemble or otherwise affect the natural
chemicals of the...
DRUG SPECIFICITY
Specificity is reciprocal:
Individual classes of drug bind only to certain
targets, and individual target...
Targets for drug action
•Receptor
•Ion channels
•Enzymes
•Carrier molecules
Four kinds
of regulatory
protein
involved as
p...
Targets for drug action
ION CHANNELS
Ligand gated ion channels –incorporate a
receptor and open or close only when the
receptor is occupied by an ...
ENZYMES
Many drugs target enzymes.
Often the drug molecule is a substrate
analogue that act as a competitive inhibitor of
...
CARRIER MOLECULE
 The transport across cell membranes of ions and
organic molecules generally requires a carrier
protein ...
RECEPTOR
 Receptor are the sensing elements in the system of
chemical communications that coordinates the function
of all...
Drug and receptor
Drugs, as well as hormones,
neurotransmitter, autacoids and toxins can
make possible the transfer of inf...
DRUG RECEPTOR
INTERACTION
Occupation of receptor by a drug molecule may or may not
result in activation of the receptor.
Drug-Receptor Interactions
Drug-receptor interactions serve as signals to trigger a cascade of
events. This cascade or si...
Classification of Receptors
IUPHAR (International Union of Pharmacological Science)
Pharmacological
Mediator (i.e. Insulin...
RECEPTOR SUPERFAMILIES
 LIGAND- GATED ION CHANNELS
 G-PROTEIN COUPLED RECEPTORS
 KINASE LINKED RECEPTORS
 NUCLEAR RECE...
 Type- Ionotropic receptors
 Location-cell membrane
 Effector-ion channel
 Coupling-direct
 Examples-Fast neurotransm...
LIGAND GATED ION CHANNELS
GATING MECHANISM
Neurotransmitter
Post synaptic membrane inotropic receptor (LGIC)
Increased permeability of ions
Depolari...
STRUCTURE OF ACH NICOTINIC
RECEPTOR
GABAA RECEPTOR
GABAA RECEPTOR
GABA
metabolites
Succinic
Semialdehyde
GT: GABA transaminase SSD: Succinic semialdehyde dehydrogenase
GT
SSD
Cl-
G – PROTEIN COUPLED
RECEPTORS
 Type: Metabotropic
 Location: Cell membrane
 Coupling: G-protein
 Exampels-
 Muscarini...
SIGNAL TRANSDUCTION
CLASSES OF G-PROTEINS
 Gs
 Gi
 Gq
 Go
Amplification………..?
Receptor Signaling Pathways
Adenylate Cyclase (AC)
Guadenylyl Cyclase (GC)
Phospholipase C (PLC)
Phospholipase A (PLA2)
Ni...
Adenylate Cyclase
 ATP cAMP Activation of PK
Phosphorylation of
cell proteins
5AMP
Enzymes involved in energy metabolism,...
REGULATION OF ENERGY BY
CAMP
PHOSPHOLIPASE C
ION CHANNELLS AS TARGET
FOR G- PROTEINS
 GPCR controls ion channels directly by
mechanism that they do not involve second...
KINASE LINKED RECEPTORS
 Mediate the actions of wide variety of proteins
mediators including growth factors, cytokines &
...
SIGNAL TRANSDUCTION
Receptor
Ligand binding
Dimerisation of receptor
Autophosporylation of tyrosine residue
Binding of int...
NUCLEAR RECEPTORS
 Nuclear receptors regulate gene transcription.
 Nuclear receptor-a misnomer as they are located
in th...
Steroid
Receptor
Confomational change
Dimer
Move to nucleus and bind to hormone – responsive elements
Increase RNA Polymer...
NUCLEAR RECEPTORS
RECEPTOR SUPERFAMILIES
RECEPTOR SUPERFAMILIES
DESENSITISATION &
TACHYPHYLAXIS
Definition:
 TACHYPHYLAXIS
The effect of a drug gradually diminishes when it is given
con...
MECHANISMS
 Loss or change in receptors
 Exhaustion of mediators
  metabolic degradation
 Physiological adaptation
 ...
Drug-Receptor Interactions
Theory and assumptions of drug-receptor interactions.
 Drug Receptor interaction follows simpl...
Agonism and Antagonism
Cont..
AGONIST: Binding + Activation
Agonists facilitate receptor response
ANTAGONIST: If a drug binds to the receptor wit...
PARTIAL & FULL AGONIST
Partial Agonists
 Full agonists  max
response
 Full response @ ~20%
occupancy
 Partial agonists 
sub maximal
response...
Comparison of Affinity & Efficacy of
Ligands
Ligand Affinity Efficacy
Agonist ++++ ++++
Antagonist ++++ -
Partial agonist ...
TWO STATE MODEL
 The receptor shows the two conformational
stage resting (R) and activated (R*) which exist
in equilibriu...
In the presence of ligand (A) equilibrium will
depend on equilibrium constant i.e. /.
 For pure antagonist it is zero.
...
R+D=
DRUG ANTAGONISM
 The effect of one drug is diminished or completely
abolished in the presence of another.
CLASSIFICATION
...
Cont…
CHEMICAL ANTAGONISM
 Two substances combine in solution and effect of active drug is
lost, e.g. Dimercaprol bind to...
REVERSIBLE COMPETITIVE ANTAGONISM
•Antagonist binds receptor but does not activates it.
•Incr’d [agonist] restores tissue ...
Antagonism-Competitive
IRREVERSIBLE COMPETITIVE ANTAGONISM
•In this antagonist dissociates very slowly or not at
all resulting in no change in an...
IRREVERSIBLE COMPETITIVE ANTAGONISM
NONCOMPETITIVE ANTAGONISM
 Antagonists blocks at some points chain of events that
lead to production of response by agoni...
Drug Receptors intercaction and Drug antagonism : Dr Rahul Kunkulol's Power point preparations
Drug Receptors intercaction and Drug antagonism : Dr Rahul Kunkulol's Power point preparations
Drug Receptors intercaction and Drug antagonism : Dr Rahul Kunkulol's Power point preparations
Drug Receptors intercaction and Drug antagonism : Dr Rahul Kunkulol's Power point preparations
Drug Receptors intercaction and Drug antagonism : Dr Rahul Kunkulol's Power point preparations
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Drug Receptors intercaction and Drug antagonism : Dr Rahul Kunkulol's Power point preparations

  1. 1. RECEPTORS AND RECEPTOR SUPERFAMILIES Dr.Rahul Kunkulol Asso. Professor dept. of Pharmacology RMC,LONI
  2. 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. 3. Drugs Drugs can be defined as agents that uniquely interact with specific target molecules in the body, thereby producing a biological effect.
  4. 4. Drugs can be stimulatory or inhibitory
  5. 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. 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. 7. Targets for drug action •Receptor •Ion channels •Enzymes •Carrier molecules Four kinds of regulatory protein involved as primary drug targets.
  8. 8. Targets for drug action
  9. 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. 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. 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. 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. 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. 14. DRUG RECEPTOR INTERACTION Occupation of receptor by a drug molecule may or may not result in activation of the receptor.
  15. 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. 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. 17. RECEPTOR SUPERFAMILIES  LIGAND- GATED ION CHANNELS  G-PROTEIN COUPLED RECEPTORS  KINASE LINKED RECEPTORS  NUCLEAR RECEPTORS
  18. 18.  Type- Ionotropic receptors  Location-cell membrane  Effector-ion channel  Coupling-direct  Examples-Fast neurotransmitters :  Nicotinic Ach  Glutamate  GABAA, LIGAND GATED ION CHANNELS
  19. 19. LIGAND GATED ION CHANNELS
  20. 20. GATING MECHANISM Neurotransmitter Post synaptic membrane inotropic receptor (LGIC) Increased permeability of ions Depolarization Action potential
  21. 21. STRUCTURE OF ACH NICOTINIC RECEPTOR
  22. 22. GABAA RECEPTOR
  23. 23. GABAA RECEPTOR
  24. 24. GABA metabolites Succinic Semialdehyde GT: GABA transaminase SSD: Succinic semialdehyde dehydrogenase GT SSD Cl-
  25. 25. G – PROTEIN COUPLED RECEPTORS  Type: Metabotropic  Location: Cell membrane  Coupling: G-protein  Exampels-  Muscarinic, Adrenergic,  Opioid, Dopamine,  5HT,Peptides,Purines
  26. 26. SIGNAL TRANSDUCTION
  27. 27. CLASSES OF G-PROTEINS  Gs  Gi  Gq  Go Amplification………..?
  28. 28. 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-
  29. 29. 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
  30. 30. REGULATION OF ENERGY BY CAMP
  31. 31. PHOSPHOLIPASE C
  32. 32. 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
  33. 33. 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.
  34. 34. SIGNAL TRANSDUCTION Receptor Ligand binding Dimerisation of receptor Autophosporylation of tyrosine residue Binding of intracellular proteins Gene transcription
  35. 35. 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.
  36. 36. Steroid Receptor Confomational change Dimer Move to nucleus and bind to hormone – responsive elements Increase RNA Polymerase activity Production of specific m RNA
  37. 37. NUCLEAR RECEPTORS
  38. 38. RECEPTOR SUPERFAMILIES
  39. 39. RECEPTOR SUPERFAMILIES
  40. 40. 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.
  41. 41. MECHANISMS  Loss or change in receptors  Exhaustion of mediators   metabolic degradation  Physiological adaptation  Active extrusion of drug from cell
  42. 42. 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.
  43. 43. Agonism and Antagonism
  44. 44. 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.
  45. 45. PARTIAL & FULL AGONIST
  46. 46. Partial Agonists  Full agonists  max response  Full response @ ~20% occupancy  Partial agonists  sub maximal response  100% occupancy  ~40% response
  47. 47. Comparison of Affinity & Efficacy of Ligands Ligand Affinity Efficacy Agonist ++++ ++++ Antagonist ++++ - Partial agonist ++++ ++
  48. 48. 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.
  49. 49. 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
  50. 50. R+D=
  51. 51. 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
  52. 52. 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.
  53. 53. 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.
  54. 54. Antagonism-Competitive
  55. 55. 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
  56. 56. IRREVERSIBLE COMPETITIVE ANTAGONISM
  57. 57. 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.

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