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Receptors as Drug Targets


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Receptor, Pharmacology

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Receptors as Drug Targets

  1. 1. Receptors as Drug Targets Capt. Htet Wai Moe 1
  2. 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. 2
  3. 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. 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 4
  5. 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. 5
  6. 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 6
  7. 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 7
  8. 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 8
  9. 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. 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. 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) 11
  12. 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 12
  13. 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. 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 14
  15. 15. Fig. Ion channel Receptors 15
  16. 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. 16
  17. 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 17
  18. 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. 18
  19. 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 19
  20. 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 20
  21. 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 21
  22. 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+ 22
  23. 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. 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 24
  25. 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 25
  26. 26. Major functional pathways of G-protein coupled receptor transduction
  27. 27. Diagrammatic representation of GPCR molecule
  28. 28. 28
  29. 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) 29
  30. 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. 31. Kinase - Linked receptor 31
  32. 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. 32
  33. 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. 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. 34
  35. 35. 35 Fig. Operational scheme of intracellular (glucocorticoid) receptor
  36. 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 36
  37. 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 37
  38. 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 38
  39. 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 39
  40. 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 40
  41. 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. 41
  42. 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. 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. 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 44
  45. 45. A B R max Response Log concentration Drug A is more potent than Drug B 45
  46. 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. 46
  47. 47. A B Response Log Concentration Drug A is more efficacious than Drug B 47
  48. 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. 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. 50
  51. 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. 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. 53
  54. 54. Non-competitive or Non-surmountable  Antagonists that covalently bind to target site  The effect cannot be overcome by more drug (agonist). 54
  55. 55. 55
  56. 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. 56
  57. 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. 57
  58. 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 58
  59. 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) 59
  60. 60. Supersensitivity can result from;  unmasking of receptors  synthesis and recruitment of new receptors (up-regulation)  accentuation of signal amplification by the transducer 60
  61. 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) 61
  62. 62. 62 THANK YOU!!!