Drug receptors in pharmacology

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  • Drug receptors in pharmacology

    1. 2. Presented by P.Bindu, M.Pharmacy 1 st year, Department of Pharmacology, Sri padmavathi mahila viswavidyalayam, Tirupati.
    2. 3. CONTENTS <ul><li>I ntroduction - receptor </li></ul><ul><li>Drug – receptor interactions </li></ul><ul><li>Ligand gated ion channel re ceptors </li></ul><ul><li>G – protein coupled receptors </li></ul><ul><li>Kinase liked receptors </li></ul><ul><li>Nuclear receptors </li></ul><ul><li>Comparison of receptor types </li></ul><ul><li>Conclusion </li></ul><ul><li>References </li></ul>
    3. 4. WHAT IS A RECEPTOR? <ul><li>Paul Ehrlich </li></ul><ul><li>Specialized areas of cell to which drugs get bound. </li></ul><ul><li>They are regulatory protein macro molecules . </li></ul><ul><li>drug should have – selectivity to a receptor ; receptor should have - ligand specificity to elicit action. </li></ul>
    4. 5. DRUG RECEPTOR INTERACTIONS <ul><li>Effect of drug attributed to two factors </li></ul><ul><li>Affinity : tendency of the drug to bind to receptor and form D-R complex . </li></ul><ul><li>Efficacy or intrinsic activity : ability of the drug to trigger pharmacological responses after forming D-R complex . </li></ul>
    5. 6. CONTD… <ul><li>Based on affinity and intrinsic activity : </li></ul><ul><li>Full agonist : high affinity </li></ul><ul><li>high intrinsic activity(=1) </li></ul><ul><li>Eg . Methacholine on acetylcholine receptors </li></ul><ul><li>Antagonist : only affinity </li></ul><ul><li>no intrinsic activity (=0) </li></ul><ul><li>Eg. Atropine on muscarinic receptors </li></ul>
    6. 8. CONTD.. <ul><li>Partial agonist : full affinity </li></ul><ul><li>intrinsic activity <1 (0 to 1) </li></ul><ul><li>Eg. Naloxene on opioid receptors </li></ul><ul><li>saralasin on angiotensin receptors </li></ul><ul><li>Inverse agonist : full affinity </li></ul><ul><li>intrinsic activity<0(0 to-1) </li></ul><ul><li>Eg. Beta carbolines on BZP receptor. </li></ul>
    7. 10. RECEPTOR CLASSIFICATION - IUPHAR <ul><li>Inotropic. </li></ul><ul><li>Metabotropic. </li></ul><ul><li>Ligand regulated trans membrane. </li></ul><ul><li>Nuclear receptors . </li></ul><ul><li>Cell surface </li></ul><ul><li>Intracellular </li></ul>
    8. 11. <ul><li>Also called ionotropic receptors. </li></ul><ul><li>involved mainly in fast synaptic transmission. </li></ul><ul><li>Eg: nAchR, GABA A , and glutamate receptors of the NMDA, AMPA and kainate types. </li></ul>
    9. 12. FEATURES – ION CHANNELS <ul><li>Protein molecules form water filled </li></ul><ul><li>pores that span the membrane. </li></ul><ul><li>Switch between open and closed states. </li></ul><ul><li>Rate and Direction of movement depends on electrochemical gradient of the ions </li></ul>
    10. 13. MOLECULAR STRUCTURE <ul><li>ligand binding site in extracellular domain. </li></ul><ul><li>4 subunits α, β, γ and δ. </li></ul><ul><li>α 2 , β, γ - pentameric str - 2 ligand binding sites </li></ul><ul><li>Each subunit spans the membrane 4 times; all subunits form a central pore . </li></ul>
    11. 14. Ligand binding site
    12. 19. GATING MECHANISM IN GABA A RECEPTOR
    13. 20. CONTD . <ul><li>Due to the concentration changes of different ions the following effects are seen. </li></ul><ul><li>Increase in Na and Ca levels- excitatory </li></ul><ul><li>Decrease in Na and Ca levels- inhibitory </li></ul><ul><li>Increase in K levels – inhibitory </li></ul><ul><li>Decrease in K levels – excitatory </li></ul><ul><li>Increase in Cl levels – inhibitory </li></ul><ul><li>Decrease in Cl levels- excitatory </li></ul>
    14. 21. ION CHANNELS - IMPORTANCE <ul><li>Generation , propagation of nerve impulse . </li></ul><ul><li>Synaptic transmission of neurons. </li></ul><ul><li>Muscle contraction. </li></ul><ul><li>Salt balance. </li></ul><ul><li>Hormone release. </li></ul><ul><li>Muscle relaxants , anti-arrhythmatics ,anesthetics – act by blocking ion channels. </li></ul>
    15. 22. <ul><li>metabotropic or 7-transmembrane-spanning (heptahelical) receptors. </li></ul><ul><li>coupled to intracellular effector systems via a G-protein. </li></ul><ul><li>mAChRs, adrenoceptors, dopamine, 5-HT, opiate , peptide, purinoceptors, orphans . </li></ul>
    16. 23. MOLECULAR STRUCTURE
    17. 24. FAMILIES OF GPCR <ul><li>3 families: </li></ul><ul><li>A – rhodopsin family </li></ul><ul><li>eg. Amine NT, purines , cannabinoids </li></ul><ul><li>B - secretin/glucagon receptor family Eg. Peptide hormones. </li></ul><ul><li>C - metabotropic glutamate receptor/calcium sensor family. </li></ul><ul><li>Eg. GABA B , Glutamate. </li></ul>
    18. 25. G-PROTEIN -ROLE <ul><li>Membrane resident proteins – recognize activated GPCRs- pass message to effector system. </li></ul><ul><li>Occurs in interaction with guanine nucleotides ; freely moving in cytoplasm. </li></ul><ul><li>α, β and γ subunits – trimer in resting state. </li></ul><ul><li>3 subunits attached to GPCR through fatty acid chain – reaction called prenylation. </li></ul>
    19. 28. G-PROTEIN SUBTYPES G-PROTEIN RECEPTOR FOR SIGNALLING PATHWAY G S Beta adrenergic amines, glucagon histamine, serotonin <ul><li>Adenylyl cyclase </li></ul><ul><li>CAMP </li></ul><ul><li>Excitatory effects </li></ul>G i1, G i2 , G i3 Alpha 2 adrenergic amines, mAchR, opioid, serotonin adenylyl cyclase CAMP Cardiac K + channel open- heart rate G olf Olfactory epithelium Adenylyl cyclase – CAMP
    20. 29. G-PROTEIN RECEPTOR FOR SIGNALLING PATHWAY G O NT ,Opioid cannabinoid Not clear G q mAchR, serotonin 5HT 1C PLC IP 3 , DAG Cytoplasmic Ca G t1 , G t2 Rhodopsin and colour opsins in retinal rod and cone cells cGMP phosphodiesterase- cGMP
    21. 30. SECONDARY MESSENGER SYSTEMS INVOLVED IN SIGNAL TRANSDUCTION <ul><li>The adenyly cyclase / cAMP system </li></ul><ul><li>The Phospholipase C / inositol phosphate system </li></ul><ul><li>The Ion channels </li></ul><ul><li>The Rho A /Rho kinase system </li></ul>
    22. 31. ADENYLYL CYCLASE/ CAMP SYSTEM <ul><li>c AMP –nucleotide synthesized from ATP - by adenylyl cyclase , metabolized by PDE. </li></ul><ul><li>Regulate enzymes of metabolism, growth, contractile proteins of muscle. </li></ul><ul><li>NT - acts on GPCR –G s /G i activated - produce effects – by inc or dec. activity of adenylyl cylase-and cAMP. </li></ul><ul><li>c AMP- activate - Protein kinases- activate/inactivate enzymes by phosphorylation – cellular events. </li></ul>
    23. 33. PHOSPHOLIPASE C-INOSITOL SYSTEM <ul><li>Phospholipase C : Cleaves membrane phospholipids - phosphoinositides . </li></ul><ul><li>PLC beta – cleaves phosphatidylinositol(4,5)bis Phosphate PIP 2 - into DAG and IP 3 . </li></ul><ul><li>DAG and IP 3 - Secondary messenegers – elicit cellular responses. </li></ul>
    24. 35. ION CHANNELS <ul><li>GPCR- directly control ion channel-without secondary messenger . Eg. mAchR in heart – activate K + channel. </li></ul>
    25. 36. RHO A / RHO KINASE SYSTEM
    26. 37. <ul><li>Involved in growth, proliferation, differentiation or survival-called growth factors. </li></ul><ul><li>Mediate actions of protein mediators- GF , cytokines , harmones- insulin and leptin . </li></ul><ul><li>Slow – require the expression of new genes. </li></ul><ul><li>Single membrane spanning helix - extracellular ligand binding domain - intracellular domain. </li></ul>
    27. 38. Structure of Kinases linked receptors Y Y Y Y Y Y Extracellular domain Binds to the ligand (growth factor) Trans membrane domain Intracellular domain Endogenous kinases bind and get phosphorlated
    28. 39. TYPES <ul><li>receptor tyrosine kinases </li></ul><ul><li>Eg. EGF , NGF , insulin receptor </li></ul><ul><li>serine/ threonine kinases </li></ul><ul><li>Eg. TGF </li></ul><ul><li>cytokine receptors </li></ul><ul><li>Eg. Cytokines , CSF </li></ul><ul><li>guanylyl cyclase receptors </li></ul><ul><li>Eg. ANP </li></ul>
    29. 40. Kinase cascade Gene transcription
    30. 41. <ul><li>Important pathways activated : </li></ul><ul><li>1. The Ras/Raf/mitogen- activated protein (MAP) kinase pathway </li></ul><ul><li>- activated by tyrosine kinases . </li></ul><ul><li>- important in cell division, growth, differentiation. </li></ul><ul><li>2. The Jak/Stat pathway </li></ul><ul><li>- activated by cytokines . </li></ul><ul><li>-controls synthesis and release of inflammatory mediators. </li></ul>
    31. 42. <ul><li>Ligand activated transcription factors . </li></ul><ul><li>Present in soluble form – either in cytoplasm or nucleus – freely diffusable. </li></ul><ul><li>Transduce signals by- modifying gene transcription . </li></ul><ul><li>Eg: steroid hormones, glucocorticoids, vit D and A, orphan receptors </li></ul><ul><li>Play vital role in endocrine signaling and metabolic regulation. </li></ul>
    32. 43. Zn fingers;hor response elements -Binds with corepressor coactivator ptns AF 1 AF 2
    33. 44. Class I Hybrid class Class II Present in cytoplasm Mainly endocrine Present in nucleus <ul><li>Form homodimers </li></ul><ul><li>Mainly endocrine; </li></ul><ul><li>Associated with heat shock proteins. </li></ul><ul><li>Form hetero dimers with RXR </li></ul><ul><li>Form hetero dimers with RXR </li></ul><ul><li>Mainly lipids </li></ul><ul><li>Associated with co-repressor proteins. </li></ul>High affinity binding Low affinity binding GR, MR, ER, PR, AR TR, VDR, RAR PPAR, LXR, FXR, RXR
    34. 45. homo HRE- hormone response elements CLASS - I
    35. 46. CLASS II
    36. 47. COMPARISON OF RECEPTORS TYPES INOTROPIC METABOTROPIC KINASE LINKED NUCLEAR NO.OF FAMILIES 483 217 135 48 LOCATION MEMBRANE MEMBRANE MEMBRANE INTRACELLULAR TIME SCALE MILLI SECONDS SECONDS HOURS HOURS COUPLING DIRECT VIA G-PROTIEN DIRECT VIA DNA EXAMPLES nAchR, GABA A ADRENOCEPTORS, mAchR INSULIN CYTOKINES GF STEROIDS
    37. 48. CONCLUSION <ul><li>Extensive research done on Receptor pharmacology -lead to discovery of new drug targets for treatment of several diseases. </li></ul><ul><li>Still requires discovery of new receptor types and the mechanisms of many orphan receptors that can result in effective treatment of many diseases. </li></ul><ul><li>Requires development of receptor crystallization etc. </li></ul><ul><li>Much to be discovered about the nuclear receptors. </li></ul>
    38. 49. REFERENCES <ul><li>Rang , Dale, Ritter ,Flower :Rang and Dale’s pharmacology;6 th edition, Churchill Livingstone;2008, 9-52. </li></ul><ul><li>Bertram G.Katzung : Basic and clinical pharmacology; 10 th edition;2006. </li></ul><ul><li>KD Tripati: essentials of medical pharmacology ; 6 th edition; 2008, 40-52. </li></ul>

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