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Nuclear receptors as target of new drug therapy

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Habibur Rahman
Habibur Rahman

Health & MedicineTechnology
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NUCLEAR RECEPTORS FOR DEVELOPING NEW DRUG THERAPY By MD. HABIBUR RAHMAN, M.Pharm. Asst. Professor, Dept. of Pharmacology. Anurag Pharmacy College, Kodad, Nalgonda (Dt), A. P
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Functions of Receptors: ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Historical background of receptor: ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],John Newport Langley( 1856-1926) An English Physiologist Paul Ehrlich (1854-1915) A German Microbiologist
Types of RECEPTORS: ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
How does Cell surface Receptor elicits its action: Cell Membrane Unbound Endogenous Activator (Agonist) of Receptor Inactive Cell Surface Receptor Extracellular Compartment Intracellular Compartment N.B : Receptors are Present in equilibrium state of active and inactive conformation. Agonists binds with the active conformations.
Extracellular Compartment Intracellular Compartment Cell Membrane Bound Endogenous Activator (Agonist) of Receptor Active Cell Surface Receptor Cellular Response
Cell Membrane Displaced Endogenous Activator (Agonist) of Receptor Inactive Cell Surface Receptor Extracellular Compartment Intracellular Compartment Bound Antagonist of Receptor (Drug) N.B: Antagonist binds to the inactive conformations of the receptor.
How does Enzyme Receptor elicit its action: Active Enzyme Substrate Product Cellular Function Inactive Enzyme Substrate Bound Enzyme Inhibitor (Drug)
NUCLEAR RECEPTOR : ,[object Object],[object Object],[object Object]
How does Nuclear Receptor elicit its action: Intracellular Compartment Nucleus DNA Modulation of Transcription Active Nuclear Receptor Bound Endogenous Activator (Agonist) of Nuclear Receptor
 
Displaced Endogenous Activator (Agonist) of Nuclear Receptor Intracellular Compartment Nucleus DNA Bound Antagonist of Receptor (Drug) Inactive Nuclear Receptor In Cytosolic Compartment Inactive Nuclear Receptor In Nuclear Compartment
Classification of nuclear receptors : ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Why Nuclear Receptor is preferred: ,[object Object],[object Object]
Differences of between Nuclear Receptors and other types of receptors: Other Types of Receptors Nuclear Receptors 1.They present in different sites of tissues and cells and bind and elicit without involvement of nucleus. 2. Elicit pharmacological response due to release/inhibition of endogenous mediators. ( transmitter, hormones, autacoids). 3.Drugs acts by modulating the receptor to produce/inhibit the release of mediators. 4. They shows changes in physiological parameters, ,[object Object],[object Object],[object Object],[object Object]
Functions of Nuclear receptor: ,[object Object],[object Object],[object Object],[object Object],[object Object]
Nuclear Receptors in Therapy: ,[object Object],[object Object]
PPAR (Peroxisome proliferators activated receptor) ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Gene transcription cartoon showing interactions of ligand/PPAR/RXR heterodimer with cofactors and basal transcription machinery(RNA Polymerase II).
GR ( Glucocorticoid Receptors): ,[object Object],[object Object],[object Object],[object Object]
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Immunosuppressive activity of GR ,[object Object],[object Object],[object Object],[object Object],[object Object]
Xeroreceptors targets for Liver Disease ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
[object Object],[object Object],[object Object],[object Object]
Nuclear Receptor Targets of Cancer Therapy: ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Estrogen Receptor and Cancer ,[object Object],[object Object],Structure of estrogen
[object Object],[object Object],[object Object],[object Object],[object Object]
SERM and Breast Cancer therapy: ,[object Object],[object Object],[object Object],[object Object]
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
[object Object],[object Object],[object Object],[object Object],Vitamin D receptor (VDR) and Postmenopauseal breast cancer:
VDR in Breast cancer therapy in post menopausesal women: ,[object Object],[object Object],[object Object],[object Object],[object Object]
VDR and Colorectal Cancer: ,[object Object],[object Object],[object Object],[object Object]
Pathogenesis: Diet with high fat Bile acid ( Lithocholic acid) poorly reabsorbed A toxic metabolite in enterohepatic circulation High conc. In colon Induce DNA strand breakage, inhibit DNA repair enzyme Colon Cancer
Pharmacology of VDR in colon cancer Vit-D VDR LCA Catabolism of CYP3A, a target gene Increased detoxification of LCA and elimination Protection against colon cancer.
 
[object Object],Receptor type Ligands / Drug Disease target PPAR α PPAR γ PPAR γ GR LXR ER ( SERM) ER β Fibrates : Clofibrate Gemfibrozil Fenofibrate Thiazolidinediones Roziglitazone Pioglitazone Perflurooctanoic acid RS544 Dexamethasone Prednisolone TO901317 Tamoxifen Raloxifen Mifepristone( Antagonist) Diabetes Type2, Hyperlipidemia. Diabetes Type2, Hyperlipidemia Atherosclerosis Anaplastic cancer Different inflammatory syndromes. Alzheimer Disease Breast cancer, Osteoporosis Unwanted abortion
Conclusion: ,[object Object],[object Object],[object Object]
References: ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
 

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Nuclear receptors as target of new drug therapy

  • 1. NUCLEAR RECEPTORS FOR DEVELOPING NEW DRUG THERAPY By MD. HABIBUR RAHMAN, M.Pharm. Asst. Professor, Dept. of Pharmacology. Anurag Pharmacy College, Kodad, Nalgonda (Dt), A. P
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  • 6. How does Cell surface Receptor elicits its action: Cell Membrane Unbound Endogenous Activator (Agonist) of Receptor Inactive Cell Surface Receptor Extracellular Compartment Intracellular Compartment N.B : Receptors are Present in equilibrium state of active and inactive conformation. Agonists binds with the active conformations.
  • 7. Extracellular Compartment Intracellular Compartment Cell Membrane Bound Endogenous Activator (Agonist) of Receptor Active Cell Surface Receptor Cellular Response
  • 8. Cell Membrane Displaced Endogenous Activator (Agonist) of Receptor Inactive Cell Surface Receptor Extracellular Compartment Intracellular Compartment Bound Antagonist of Receptor (Drug) N.B: Antagonist binds to the inactive conformations of the receptor.
  • 9. How does Enzyme Receptor elicit its action: Active Enzyme Substrate Product Cellular Function Inactive Enzyme Substrate Bound Enzyme Inhibitor (Drug)
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  • 11. How does Nuclear Receptor elicit its action: Intracellular Compartment Nucleus DNA Modulation of Transcription Active Nuclear Receptor Bound Endogenous Activator (Agonist) of Nuclear Receptor
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  • 13. Displaced Endogenous Activator (Agonist) of Nuclear Receptor Intracellular Compartment Nucleus DNA Bound Antagonist of Receptor (Drug) Inactive Nuclear Receptor In Cytosolic Compartment Inactive Nuclear Receptor In Nuclear Compartment
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  • 26. Gene transcription cartoon showing interactions of ligand/PPAR/RXR heterodimer with cofactors and basal transcription machinery(RNA Polymerase II).
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  • 40. Pathogenesis: Diet with high fat Bile acid ( Lithocholic acid) poorly reabsorbed A toxic metabolite in enterohepatic circulation High conc. In colon Induce DNA strand breakage, inhibit DNA repair enzyme Colon Cancer
  • 41. Pharmacology of VDR in colon cancer Vit-D VDR LCA Catabolism of CYP3A, a target gene Increased detoxification of LCA and elimination Protection against colon cancer.
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