EICOSANOIDS & PROTAGLANDINS.pptx. .

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1. EICOSANOIDS & PROTAGLANDINS SUBJECT: ADVANCES IN MEDICINAL CHEMISTRY SUBMITTED BY Shah Alam (Y23254020) M pharm 2 nd sem SUBMITTED TO PROF. ASMITA GAJBHIYE PROF SUSHIL K KASHAW MR SATYAMSHYAM VISHWAKARMA MR PRIYANSHU NEMA DEPARTMENT OF PHARMACEUTICAL SCIENCES Dr. HARI SINGH GOUR VISHWAVIDYALAYA SAGAR (M.P.) 470003 (A CENTRAL UNIVERSITY)

2. OVERVIEW • INTRODUCTION • CLASSIFICATION • SYNTHESIS • REGULATION & INHIBITION • FUNCTIONS • BIOLOGICAL ACTIONS AND CLINICAL APPLICATIONS • REFRENCES

3. EICOSANOIDS They are 20 carbon compound (Greek eikosi = twenty). They are made from arachidonic acid or other polyunsaturated fatty acids They are synthesized in most cells and are potent regulators of cellular function Eicosanoids act as local (autocrine paracrine) hormones They are extremely potent compound that elict a wide range of responses boath physiologic (inflammatory response )and pathologic (hyper-sensitivity) The most important are Prostaglandins, Thromboxanes and Leukotrienes

4. CLASSIFICATION

5. PROSTAGLANDINS 1st discovered in human semen by Ulf Von Euler in 1930; were found to stimulate uterine contraction and reduce blood pressure Prostaglandins (PGs) structurally resemble prostanoic acid, a 20-carbon fatty acid Prostanoic acid has a five-carbon ring and two side chains attached to the ring Presumed to be synthesized by prostate gland hence the name. Later realized were synthesized in all tissues except erythrocytes. This has a cyclopentane ring (formed by carbon atoms 8 to 12) and two side chains, with carboxyl group on one side Prostaglandins differ in their structure due to substituent group and double bond on cyclopentane ring

6. PROSTAGLANDINS - NOMENCLATURE Abbreviated as PG, with the class designated by a capital letter A,B,D,E,F,G,H and I , followed by a number. PGE and PGF; 1st isolated from the biological fluids The most important prostaglandins are types E and F Prostaglandins of type E are PGE1, PGE2 and PGE3 Prostaglandins of type F are PGF1 PGF2 and PGF30 The letters refer to the different ring structure, except in PGG and PGH: same ring structure (cyclo endohydroperoxide) In the same series, depending upon double bonds on the side chains designated as PGE1, PGE2, PGE3 ..etc PGD2, PGE2, PGF2 and PGI2 and thromboxane A2 are widely distributed.

7. THROMBOXANES (TXS) Named so because they are identified first in thrombocytes Structure is similar to PGs, but have an oxygen atom in the cyclic ring and contains a six numbered heterocyclic oxane ring. The most common thromboxane, TXA2, contains an additional oxygen atom attached both to carbon 9 and carbon 11 of the ring TXA2- Vasoconstriction and platelet aggregation thus helping clot formation. Inhibited by aspirin. TXB2- a stable degradation product of TxA2, plays a role in acute hepatoxicity induced by acetaminophen

8. CYCLOOXYGENASE PATHWAY-CYCLIC PATHWAY (SYNTHESIS OF PROSTAGLANDINS AND THROMBOXANES) 1st described by Scene Bergstrom and Bengt Samuelsson (1960)Recommended Occurs in endoplasmic reticulam In humans, the most important precursor for prostaglandins is → arachidonic acid, a polyunsaturated fatty acid with four double bonds (eicosatetraenoic acid). It is stored in cell membranes as the C2 ester of phosphatidylinositol and other phospholipids The dietary precursor of the prostaglandins is the essential fatty acid, linoleic acid Site: In all types of mammalian cells except RBCs (No cyclooxygenase activity has been found in human RBCs)

9. 1 . RELEASE OF ARACHIDONIC ACID : Arachidonic acid is incorporated into membrane-bound phospholipids Initially, Arachidonic acid is released from these phospholipids by phospholipase A2 in response to a variety of signals .It is activated by hormones like epinephrin, bradykinin etc.

10. 2. SYNTHESIS OF PGH2 1st step in prostgladin synthesis is oxidative cyclization of free arachidonic adid to yield PGH₂ by prostagladin endoperoxide synthase (PGH Synthase) PGH synthase exhibits 2 catalytic activities : Cyclooxygenase (COX ) and Peroxidase o Initial step: Catalyzed by a cyclooxygenase and forms the five- membered ring with the addition of 4- atoms of oxygen. 2 between C-9 and 11, and 2 at C-15 to form an unstable endoperoxide, PGG2. The hydroperoxy group at carbon 15 of PGG2 is quickly reduced to a hydroxyl group by a peroxidase to form another endoperoxide. PGH2.

11. ISOZYMES OF PGH SYNTHASE Cyclooxygenase (COX) :Two isozymes usually denoted as COX-1 and COX-2

12. 3. CONVERSION OF PRIMARY PROSTAGLANDIN (PGH2) TO OTHER EICOSANOIDS Enzymes → cell specific, like: PGE synthase and PGD synthase and so on. Thus, vascular endothelium produces PGE and PGI, and platelets produce thromboxanes (TXs). In kidney and spleen, isomerase catalyses production of PGE2 and reductase catalyses production of PGF2.

13. THROMBOXANE Thromboxanes are highly active metabolites of the PGG2 and PGG2 type prostaglandin endoperoxides that have the cyclopentane ring replaced by a six membered oxygen containing (oxane) ring. The term thromboxane is derived from the fact that these compounds have a thrombus forming potential. Thromboxane A synthase , present in the endoplasmic reticulum, is abundant in lung and platelets and catalyzes conversion of endoperoxide PGH2 to TXA2. The half life of TXA2 is very short in water (t1/2~ 1 min) as the compound is transformed rapidly into inactive thromboxane B2 (TXB2)

14. REGULATION OF PROSTAGLANDIN SYNTHESIS INHIBITION : Cortisol- inhibits Phospholipase A2 activity NSAIDs like Aspirin, Indomethacin, Ibuprofen, phenylbutazone inhibit both COX-1 and COX-2 and, thus, prevent the synthesis of the parent prostaglandin, PGH2 These NSAIDS have side effects like gastrointestinal ulcers and renal disturbances NSAID like Celecoxib is selective COX-2 inhibitors, and thus are free from those side effects. Aspirin acetylates serine at the active site and irreversibly cyclooxygenase inhibits cyclooxygenase Other NSAIDs: act as reversible inhibitors of cyclooxygenase

15. Cyclooxygenase is a "suicide" enzyme . Self catalysed destruction rapidly inactivates the enzyme, thus preventing excessive production of PGs. OPGs have very short half life of about 30 secs . They are inactivated by 15-hydroxyl-prostaglandin- dehydrogenase (15-OH-PGDH) which converts 15-OH group to keto group. Activators: Bradykinin, epinephrine, thrombin, angiotensin II, & vasopressin. activates Phospholipase A2 Catecholamines activates cyclooxygenase

16. BIOLOGICAL ACTIONS AND CLINICAL APPLICATIONS OF PROSTAGLANDINS AND THROMBOXANE 1 . EFFECTS ON CVS 2. EFFECTS ON SMOOTH MUSCLE 3. UTERINE MUSCLE 4. EFFECTS ON IMMUNITY AND INFLAMMATION (HEMATOLOGICAL RESPONSE) 5. ACTS ON GI SECREATION 6. METABOLIC EFFECTS & ACTION ON ENDOCRINE ORGANS 7..RENAL ACTION

17. 1 Effects on CVS: Prostacyclin or PGI2- is synthesized by the vascular endothelium. ➤ Vasodilatation 1. inhibits platelet aggregation and has a protective effect on vessel wall against deposition of platelets. 2. Platelets attempting to stick to blood vessel wall release endoperoxidase which enhance production of prostacyclin by vascular endothelial cells 3. But any injury to the vessel wall inhibits PG12 synthesis and promotes TXA₂ synthesis which causes → vasoconstriction → and platelet aggregation. Thus, prostacyclin and thromboxane are opposing in activity

18. REFRENCES W, M. Foye "Principles of Medicinal Chemistry" Lea & Febiger Remers WA eds, Delgado J.N.,, "Wilson & Giswolds Text Book of organic Medicinal & Pharmaceutical chemistry" Lippincott, New York. Wang, J., Liu, M., Zhang, X., Yang, G. and Chen, L. (2018) Physiological and pathophysiological implications of PGE2 and the PGE2 synthases in the kidney. Prostagland. Other Med. 134, 1-6. Dennis, E.A., Cao, J., Hsu, Y.H., Magrioti, V. and Kokotos, G (2011) Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention. Chem. Rev. 111, 6130-6185.