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Nuclear receptors as target of new drug therapy

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Nuclear receptors as target of new drug therapy

  1. 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
  2. 2. <ul><li>RECEPTOR : ( Latin: means a receiver ) </li></ul><ul><li>DEFINITION: </li></ul><ul><li>A macromolecular component </li></ul><ul><li> of the organism that binds the drug </li></ul><ul><li>and initiates its effect. </li></ul><ul><li>To elicit the pharmacological </li></ul><ul><li>action , the functional group of the </li></ul><ul><li>drug have to interact with the </li></ul><ul><li> complementary chemical groupings </li></ul><ul><li>of the biologically important integral part of the organism is called receptor. </li></ul>
  3. 3. Functions of Receptors: <ul><li>Receptors regulates the:- </li></ul><ul><li>1.Enzyme activity </li></ul><ul><li>2. Permeability/Transport </li></ul><ul><li>3. Structural features </li></ul><ul><li>4. Template function </li></ul><ul><li>5. Homoeostasis </li></ul><ul><li>6. Cellular regulatory signals etc </li></ul>
  4. 4. Historical background of receptor: <ul><li>The concept of receptor is </li></ul><ul><li>first established in 1878 by </li></ul><ul><li>John N. Langley demonstrating </li></ul><ul><li>the interaction of atropine and </li></ul><ul><li>pilocarpine with cellular component </li></ul><ul><li>to elicit the action. </li></ul><ul><li>Paul Ehrlich coined the </li></ul><ul><li>cellular component as receptive </li></ul><ul><li>substance or receptor in 1907. </li></ul>John Newport Langley( 1856-1926) An English Physiologist Paul Ehrlich (1854-1915) A German Microbiologist
  5. 5. Types of RECEPTORS: <ul><li>1. Cell surface receptors </li></ul><ul><li>I. Ligand gated ion Channels) </li></ul><ul><li>eg: Nicotinic Cholinergic, GABAa </li></ul><ul><li> II. G-protein coupled receptors. </li></ul><ul><li>eg: Muscarinic, β -adrenergic, DopamineD2 </li></ul><ul><li>2. Enzyme linked receptors. </li></ul><ul><li>eg: Tyrosine Protein kinase receptor </li></ul><ul><li>3. Nuclear receptors. </li></ul><ul><li>eg:GR receptor, AR receptor, PPAR </li></ul>
  6. 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. 7. Extracellular Compartment Intracellular Compartment Cell Membrane Bound Endogenous Activator (Agonist) of Receptor Active Cell Surface Receptor Cellular Response
  8. 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. 9. How does Enzyme Receptor elicit its action: Active Enzyme Substrate Product Cellular Function Inactive Enzyme Substrate Bound Enzyme Inhibitor (Drug)
  10. 10. NUCLEAR RECEPTOR : <ul><li>Hormone receptors that bind ligand and act in the cell nucleus rather than at the cell surface and regulate gene expression. </li></ul><ul><li>Nuclear receptor is also called as true receptors which involved in increase or decrease in the production of certain RNAs and mRNA along with corresponding enzyme and protein. </li></ul><ul><li>Recent data demonstrates that these are the prototypes of a large family of receptors for small lipophilic signaling molecules including steroid hormone, fat soluble vitamins fatty acid metabolites and cholesterol metabolites. </li></ul>
  11. 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
  12. 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
  13. 14. Classification of nuclear receptors : <ul><li>The following is a list of the 48 known human nuclear receptors categorized into the following families: </li></ul><ul><li>Subfamily 1: Thyroid Hormone Receptor-like </li></ul><ul><li>Group A : Thyroid hormone receptor ( Thyroid hormone) </li></ul><ul><ul><li>1: Thyroid hormone receptor-α ( TRα ; NR1A1, THRA ) </li></ul></ul><ul><ul><li>2: Thyroid hormone receptor-β ( TRβ ; NR1A2, THRB ) </li></ul></ul><ul><li>Group B: Retinoic acid receptor ( Vitamin A and related compounds) </li></ul><ul><ul><li>1: Retinoic acid receptor-α ( RARα ; NR1B1, RARA ) </li></ul></ul><ul><ul><li>2: Retinoic acid receptor-β ( RARβ ; NR1B2, RARB ) </li></ul></ul><ul><ul><li>3: Retinoic acid receptor-γ ( RARγ ; NR1B3, RARG ) </li></ul></ul><ul><li>Group C : Peroxisome proliferator-activated receptor ( fatty acids, prostaglandins) </li></ul><ul><ul><li>1: Peroxisome proliferator-activated receptor-α ( PPARα ; NR1C1, PPARA ) </li></ul></ul><ul><ul><li>2: Peroxisome proliferator-activated receptor-β/δ ( PPARβ/δ ; NR1C2, PPARD ) </li></ul></ul><ul><ul><li>3: Peroxisome proliferator-activated receptor-γ ( PPARγ ; NR1C3, PPARG ) </li></ul></ul>
  14. 15. <ul><li>Group D : Rev-ErbA ( heme) </li></ul><ul><ul><li>1: Rev-ErbAα ( Rev-ErbAα ; NR1D1 ) </li></ul></ul><ul><ul><li>2: Rev-ErbAβ ( Rev-ErbAβ ; NR1D2 ) </li></ul></ul><ul><li>Group F : RAR-related orphan receptor(cholesterol, ATRA ) </li></ul><ul><ul><li>1: RAR-related orphan receptor-α ( RORα ; NR1F1, RORA ) </li></ul></ul><ul><ul><li>2: RAR-related orphan receptor-β ( RORβ ; NR1F2, RORB ) </li></ul></ul><ul><ul><li>3: RAR-related orphan receptor-γ ( RORγ ; NR1F3, RORC ) </li></ul></ul><ul><li>Group H: Liver X receptor -like (oxy sterol) </li></ul><ul><ul><li>3: Liver X receptor-α ( LXRα ; NR1H3 ) </li></ul></ul><ul><ul><li>2: Liver X receptor-β ( LXRβ ; NR1H2 ) </li></ul></ul><ul><ul><li>4: Farnesoid X receptor ( FXR ; NR1H4 ) </li></ul></ul><ul><li>Group I: Vitamin D receptor-like </li></ul><ul><ul><li>1: Vitamin D receptor ( VDR ; NR1I1, VDR ) ( vitamin D ) </li></ul></ul><ul><ul><li>2: Pregnane X receptor ( PXR ; NR1I2 ) ( xenobiotics ) </li></ul></ul><ul><ul><li>3: Constitutive androstane receptor ( CAR ; NR1I3 ) ( androstane ) </li></ul></ul>
  15. 16. <ul><li>Subfamily 2: Retinoid X Receptor-like </li></ul><ul><li>Group A: Hepatocyte nuclear factor-4 (HNF4) ( fatty acids ) </li></ul><ul><ul><li>1: Hepatocyte nuclear factor-4-α ( HNF4α ; NR2A1, HNF4A ) </li></ul></ul><ul><ul><li>2: Hepatocyte nuclear factor-4-γ ( HNF4γ ; NR2A2, HNF4G ) </li></ul></ul><ul><li>Group B: Retinoid X receptor (RXRα) ( retinoids) </li></ul><ul><ul><li>1: Retinoid X receptor-α ( RXRα ; NR2B1, RXRA ) </li></ul></ul><ul><ul><li>2: Retinoid X receptor-β ( RXRβ ; NR2B2, RXRB ) </li></ul></ul><ul><ul><li>3: Retinoid X receptor-γ ( RXRγ ; NR2B3, RXRG ) </li></ul></ul><ul><li>Group C: Testicular receptor </li></ul><ul><ul><li>1: Testicular receptor 2 ( TR2 ; NR2C1 ) </li></ul></ul><ul><ul><li>2: Testicular receptor 4 ( TR4 ; NR2C2 ) </li></ul></ul><ul><li>Group E: TLX/PNR </li></ul><ul><ul><li>1: Human homologue of the Drosophila tailless gene ( TLX ; NR2E1 ) </li></ul></ul><ul><ul><li>3: Photoreceptor cell-specific nuclear receptor ( PNR ; NR2E3 ) </li></ul></ul><ul><li>Group F: COUP /EAR </li></ul><ul><ul><li>1: Chicken ovalbumin upstream promoter-transcription factor I ( COUP-TFI ; NR2F1 ) </li></ul></ul><ul><ul><li>2: Chicken ovalbumin upstream promoter-transcription factor II ( COUP-TFII ; NR2F2 ) </li></ul></ul><ul><ul><li>6: V-erbA-related gene|V-erbA-related ( EAR-2 ; NR2F6 ) </li></ul></ul>
  16. 17. <ul><li>Subfamily 3: Estrogen Receptor-like: </li></ul><ul><li>Group A: Estrogen receptor ( Sex hormones : Estrogen) </li></ul><ul><ul><li>1: Estrogen receptor-α ( ERα ; NR3A1, ESR1 ) </li></ul></ul><ul><ul><li>2: Estrogen receptor-β ( ERβ ; NR3A2, ESR2 ) </li></ul></ul><ul><li>Group B: Estrogen related receptor </li></ul><ul><ul><li>1: Estrogen-related receptor-α ( ERRα ; NR3B1, ESRRA ) </li></ul></ul><ul><ul><li>2: Estrogen-related receptor-β ( ERRβ ; NR3B2, ESRRB ) </li></ul></ul><ul><ul><li>3: Estrogen-related receptor-γ ( ERRγ ; NR3B3, ESRRG ) </li></ul></ul><ul><li>Group C : 3-Ketosteroid receptors </li></ul><ul><ul><li>1: Glucocorticoid receptor ( GR ; NR3C1 ) ( Cortisol ) </li></ul></ul><ul><ul><li>2: Mineralocorticoid receptor ( MR ; NR3C2 ) ( Aldosterone ) </li></ul></ul><ul><ul><li>3: Progesterone receptor ( PR ; NR3C3, PGR ) ( Sex hormones : Progesterone ) </li></ul></ul><ul><ul><li>4: Androgen receptor ( AR ; NR3C4, AR ) ( Sex hormones : Testosterone ) </li></ul></ul>
  17. 18. <ul><ul><li>Subfamily 4: Nerve Growth Factor IB-like </li></ul></ul><ul><li>Group A: NGFIB/NURR1/NOR1 </li></ul><ul><ul><li>1: Nerve Growth factor IB ( NGFIB ; NR4A1 ) </li></ul></ul><ul><ul><li>2: Nuclear receptor related 1 ( NURR1 ; NR4A2 ) </li></ul></ul><ul><ul><li>3: Neuron-derived orphan receptor 1 ( NOR1 ; NR4A3 ) </li></ul></ul><ul><ul><li>Subfamily 5: Steroidogenic Factor-like </li></ul></ul><ul><li>Group A: SF1/LRH1 </li></ul><ul><ul><li>1: Steroidogenic factor 1 ( SF1 ; NR5A1 ) ( phospholipids ) </li></ul></ul><ul><ul><li>2: Liver receptor homolog-1 ( LRH-1 ; NR5A2 ) </li></ul></ul><ul><li> Subfamily 6: Germ Cell Nuclear Factor-like </li></ul><ul><li>Group A: GCNF </li></ul><ul><ul><li>1: Germ cell nuclear factor ( GCNF ; NR6A1 ) </li></ul></ul><ul><li>Subfamily 0: Miscellaneous </li></ul><ul><li>Group B: DAX/SHP </li></ul><ul><ul><li>1: Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 ( DAX1 , NR0B1 ) </li></ul></ul><ul><ul><li>2: Small heterodimer partner ( SHP ; NR0B2 ) </li></ul></ul><ul><li>Group C: Nuclear receptors with two DNA binding domains (2DBD-NR) (A novel subfamily) </li></ul>
  18. 19. Why Nuclear Receptor is preferred: <ul><ul><li>Nuclear receptors have the ability to directly bind to DNA and regulate the expression of adjacent genes. </li></ul></ul><ul><ul><li>Consequently nuclear receptors play key roles in both embryonic development and adult homeostasis. </li></ul></ul>
  19. 20. 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, <ul><li>They present with association of nucleus and elicit the response with involvement of nucleus. </li></ul><ul><li>2. Elicit the response on the basis of transcription of gene, regulates protein synthesis. </li></ul><ul><li>3. Drugs acts which cause the transcription of gene from its genetics based. </li></ul><ul><li>4. They shows changes on structural basis of target cells. </li></ul>
  20. 21. Functions of Nuclear receptor: <ul><li>To propagate the regulatory signals from outside to within effectors cell. </li></ul><ul><li>To amplify the signal. </li></ul><ul><li>To integrate various extracellular and intracellular regulatory signals. </li></ul><ul><li>To adapt changes and maintain homeostasis. </li></ul><ul><li>To facilitates gene expression so that specific mRNA is synthesized , which moves to ribosome and directs synthesis of specific proteins which regulates the activity of target cells. </li></ul>
  21. 22. Nuclear Receptors in Therapy: <ul><li>Nuclear Receptors are one of the major target area of modern therapy and of research. </li></ul><ul><li>A large number of receptors are identified and so screening of their Ligands are going in clinical trials as well as few of them becoming patent. </li></ul>
  22. 23. PPAR (Peroxisome proliferators activated receptor) <ul><li>Types of PPAR Receptors: </li></ul><ul><li>PPAR α expressed in Liver, Kidney, Heart, Muscle, Adipose Tissue and others. </li></ul><ul><li>PPAR β expressed mainly in brain, adipose tissue and skin. </li></ul><ul><li>PPAR γ almost all the tissue. </li></ul><ul><li>PPARs heterodimerize </li></ul><ul><li>with Liver X Receptors ( LXR), </li></ul><ul><li>or Retinoid X Receptors( RXR), </li></ul><ul><li>or Vitamin D receptors. </li></ul>
  23. 24. <ul><li>Functions: </li></ul><ul><li>Control of Cellular differentiation and Development. </li></ul><ul><li> Control of Metabolism ( Carbohydrate, Lipid, protein). </li></ul><ul><li>Genetics: </li></ul><ul><li>PPARα - chromosome22q12-13.1 (OMIM 170998 ) PPARβ/δ - chromosome 6p21.2-21.1 (OMIM 600409 ) </li></ul><ul><li>PPARγ- chromosome 3p25 (OMIM 601487 ). </li></ul><ul><li>Disease involved : Diabetes Type 2, Atherosclerosis, Obesity and Hyperlipidemia . </li></ul>
  24. 25. <ul><li>PPAR Agonists for treatment: </li></ul><ul><li>PPAR α : Fibrates ( Clofibrate, Gemfibrozil, Fenofibrate). </li></ul><ul><li>PPAR γ : Thiazolidinediones ( Roziglitazone, Pioglitazone, Perflurooctanoic acid). </li></ul><ul><li>Pharmacology: </li></ul><ul><li>Agonist Receptor Enhance Transcription of responsive genes </li></ul><ul><li>Glucose entry to muscle </li></ul><ul><li>and suppressed Reverse insulin resistance </li></ul><ul><li>Gluconeogenesis. </li></ul>
  25. 26. Gene transcription cartoon showing interactions of ligand/PPAR/RXR heterodimer with cofactors and basal transcription machinery(RNA Polymerase II).
  26. 27. GR ( Glucocorticoid Receptors): <ul><li>Physiological function: </li></ul><ul><li>GR express and regulates the genes controlling for development , metabolism and immmune response. </li></ul><ul><li>GR and LRH-1(Liver Receptor Homolog-1) upregulates the expression anti-inflamatory proteins in nucleas. </li></ul><ul><li>Disease involved : Inflammatory bowel syndrome, Auto Immune disorder, rheumatoid arthritis, gout etc. </li></ul>
  27. 28. <ul><li>Agonists : Cortisol, Prednisolone, </li></ul><ul><li>De xamethasone. </li></ul><ul><li>Genetics: NR3C1, NR5A2 , NR3C2 Gene </li></ul><ul><li>Pharmacology: ( Anti- inflammatory activity) </li></ul><ul><li>Agonist Receptor Enhance Transcription of responsive genes </li></ul><ul><li>.Inhibition of PhospolipaseA2 Production of lipocortin TNF, PAF and related proteins. </li></ul>
  28. 29. Immunosuppressive activity of GR <ul><li>Agonist Receptor Transcription of Responsive Genes </li></ul><ul><li>Decrease proliferation of Inhibition of IL synthesis. </li></ul><ul><li>B-Lymphocytes. </li></ul><ul><li>Inhibition of T-lymphocyte production Decrease antibody </li></ul><ul><li>production </li></ul>
  29. 30. Xeroreceptors targets for Liver Disease <ul><li>Xeroreceptors: </li></ul><ul><ul><ul><li>CAR ( Constitutive Androstane Receptor) </li></ul></ul></ul><ul><ul><ul><li>PXR (Pregnane X Receptors). </li></ul></ul></ul><ul><ul><ul><li>Physiological function: </li></ul></ul></ul><ul><ul><ul><li>Activation and consequences on Lipid metabolism </li></ul></ul></ul><ul><ul><ul><li>Glucose Homeostasis </li></ul></ul></ul><ul><ul><ul><li>Inflammatory Responses </li></ul></ul></ul><ul><ul><ul><li>Genetics: Targeted Genes </li></ul></ul></ul><ul><ul><ul><ul><ul><li>CYP3A4, CYP2B6, CYP2C9 </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>MDR1, GT1A1, MRP2, UGT1A1 </li></ul></ul></ul></ul></ul>
  30. 31. <ul><li>Disease Involved: </li></ul><ul><li>Non-alchoholic fatty liver, Hepatic Steatosis, </li></ul><ul><li>Obesity, Inflammation </li></ul><ul><li>Agonists : Rifampin, Nifidipine, Hyperferlin, RU486, HNF4 </li></ul>
  31. 32. Nuclear Receptor Targets of Cancer Therapy: <ul><li>Nuclear Receptors targeted </li></ul><ul><li>mainly for Cancer therapy are. </li></ul><ul><li>1.Estrogen Receptor ( ER) </li></ul><ul><li>2. Vitamin D Receptor (VDR) </li></ul><ul><li>3.PPAR γ </li></ul><ul><li>4. Androgen Receptor (AR) </li></ul><ul><li>5. Progesterone Receptor (PR) </li></ul>
  32. 33. Estrogen Receptor and Cancer <ul><li>Estrogens are key regulator of growth, differentiation, and function in large number of tissue. </li></ul><ul><li>Biological effects of estrogens are mediated by ER α and ER ß </li></ul>Structure of estrogen
  33. 34. <ul><li>Esrogen Receptors Types: </li></ul><ul><li>1: Estrogen receptor-α ( ERα ; NR3A1, ESR1 ) </li></ul><ul><ul><li>2: Estrogen receptor-β ( ERβ ; NR3A2, ESR2 ) </li></ul></ul><ul><li>ER α is predominant and expressed in breast, uterus, cervix and Vagina. </li></ul><ul><li>ER ß is predominantly localized in ovary, prostate, testis, spleen, Lung, hypothalamus and thymus. </li></ul>
  34. 35. SERM and Breast Cancer therapy: <ul><li>Pharmacology: </li></ul><ul><li>Breast cancer dependent upon the presence of estrogen for growth. </li></ul><ul><li>The objective of treatment is SERMs ( Selective estrogen receptor modulators) to inhibit tumor growth by interrupting the estrogen signaling process. </li></ul><ul><li>SERMs shows estrogenic effect in some tissue and anti estrogenic in others. </li></ul>
  35. 36. <ul><li>Tamoxifen ( Nolvadex ®, Astra Zeneca ):- </li></ul><ul><li>It has antagonistic effect in mammary tissue, while agonist effect in bone, uterine and cardiovascular tissue. </li></ul><ul><li>An ideal agents foe breast </li></ul><ul><li>cancer which retain the </li></ul><ul><li>beneficial effects of estrogen </li></ul><ul><li>in bone, brain and </li></ul><ul><li>cardiovascular tissue. </li></ul><ul><li>It inhibit the mutagenic effect of estrogen in breast. </li></ul>
  36. 37. <ul><li>Role of VDR in Breast Cancer: </li></ul><ul><li>VDR binds with 1a, 25-dihydroxy cholecalciferol D3 and regulates the transcription of Vit-D responsive gene. </li></ul><ul><li>This regulates the calcium endocrinology and involved in homeostasis such as skin, muscle, pancreas and reproductive organs. </li></ul><ul><li>Activated VDR induces genes that suppress proliferation and stimulate differentiation of cells in the normal mammary gland. </li></ul>Vitamin D receptor (VDR) and Postmenopauseal breast cancer:
  37. 38. VDR in Breast cancer therapy in post menopausesal women: <ul><li>Pathogenesis: </li></ul><ul><li>Aging reduces the production of Vitamin D by epidermis. </li></ul><ul><li>Estrogen deficiency decreases both metabolic activation of Vitamin D and expression of the VDR. </li></ul><ul><li>VDR agonists: </li></ul><ul><li>Nearly 400 structural analogs of Vit.D have been synthesized but few have advanced in clinical trials due to preliminary toxicity testing. </li></ul>
  38. 39. VDR and Colorectal Cancer: <ul><li>N.B: </li></ul><ul><li>Cancer of the large intestine (colon) and rectum, collectively termed colorectal cancer. </li></ul><ul><li>It is the third most common form of cancer, behind lung and breast cancer. </li></ul><ul><li>Vitamin D receptors is also considered as target of colon cancer along with Glucocorticoid receptor. </li></ul>
  39. 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
  40. 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.
  41. 43. <ul><li>Examples: Ligands and target Genes of some nuclear receptors: </li></ul>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
  42. 44. Conclusion: <ul><li>Functioning as transcription factors and controlling cellular process at the level of gene expression. </li></ul><ul><li>Modulation of NR activity produces selective alterations in downstream gene expression. </li></ul><ul><li>Nuclear Receptors are an attractive and relatively unexploited target for drug development. </li></ul>
  43. 45. References: <ul><li>Books: </li></ul><ul><ul><li>Essential of Medical Pharmacology, 6 th Edition </li></ul></ul><ul><li>by K. D. Tripathi, Page no. 40-53 </li></ul><ul><ul><li>Principles of Medicinal Chemistry, Volume-1, by S.S. Kadam, K,R. Mahadik, K.G. Bothara, Page no. 44-55 </li></ul></ul><ul><ul><li>Foye’s Principles of Medicinal Chemistry, Fifth Edition, Page no. 86-99. </li></ul></ul><ul><li>Web-links: </li></ul><ul><ul><li>www.google.com </li></ul></ul>

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