پایان نامه بررسی اثرات ضد التهابی مشتقات جدید سنتزشده N-آریل فتالامید

فهرست:

خلاصه فارسی................................................................................................................................................................. 1

فصل اول: کلیات

1- 1.ضرورت و اهمیت موضوع......................................................................................................................................... 3

1- 2.هدف...............................................................................................................................................................................3

فصل دوم: بررسی متون و مطالعات دیگران در این زمینه   

بخش اول:بررسی متون                                                                        

2-1-1. مقدمه.................................................................................................................................................................. ......5

2-1-2. تاریخچه.............................................................................................................................................................. ......7

2-1-3. التهاب.................................................................................................................................................................  ......7

2-1-3-1. علایم التهاب......................................................................................................................................................9

2-1-3-2. مدیاتور های التهاب.........................................................................................................................................9

2-1-3-3. پاسخ التهابی.......................................................................................................................................................9

2-1-4. ایکوزانوئیدها..........................................................................................................................................................11

2-1-4-1. تعریف.............................................................................................................................................................. 11

2-1-4-2. ساختمان و بیوسنتز......................................................................................................................................11

2-1-5. مسیر سیکلواکسیژناز..........................................................................................................................................14

2-1-5-1. پروستاگلاندین‌ها.............................................................................................................................................18

2-1-5-1-1. تاریخچه...................................................................................................................................................... 18

2-1-5-1-2. ساختمان.................................................................................................................................................... 18

2-1-5-2. اثرات بیولوژیک پروستانوئیدها................................................................................................................... 19

2-1-5-2-1. نقش پروستانوئیدها در فرآیند درد و التهاب..................................................................................... 21                                                  

2-1-6-3.آنزیم سیکلواکسیژناز  و  ایزوفرمهای  آن..................................................................................................21    

2-1-5-3-1.ساختمان بیوشیمیایی ایزوفرم‌های آنزیم سیکلو اکسیژناز..............................................................22

2-1-5-3-2.ساختمان سه بعدی آنزیم سیکلو اکسیژناز..........................................................................................23

2-1-5-3-3.جایگاه فعال سیکلواکسیژنازی.............................................................................................................. 25

2-1-5-3-4.مقایسه‌ی جایگاه فعال سیکلواکسیژنازی cox-1وcox-2 ........................................................... 27

2-1-5-3-5.مقایسه‌ی cox-1 و cox-2 دراتصال به مهارکننده‌های سیکلو اکسیژناز...................................29

2-1-5-3-6. بررسی ساختار کریستالی کمپلکس آنزیم cox-1 و مهار کننده............................................... 30

2-1-5-3-7.بررسی ساختار کریستالی کمپلکس آنزیم cox-2-مهار کننده ................................................. 31

2-1-6.مهار کننده‌های سیکلواکسیژناز..................................................................................................................... 33

2-1-6-1.مهار کننده‌های کلاسیک (غیرانتخابی).................................................................................................. 34

2-1-6-1-1.طبقه‌بندی ساختمانی مهار کنندگان غیر انتخابی آنزیم سیکلو اکسیژناز................................. 34

2-1-6-1-1-1.سالیسیلات‌ها.................................................................................................................................... 38

2-1-6-1-1-2. آریل آلکانوئیک اسیدها..................................................................................................................39

2-1-6-1-1-3. N–آریل آنترانیلیک اسید ها (فنامات ها)............................................................................... 40

2-1-6-1-1-4. انوئیک اسیدها (اکسیکامها)........................................................................................................ 41

2-6-1-2.مکانیسم مهار آنزیم سیکلو اکسیژناز توسط مهار کنندگان غیر انتخابی...................................... 42                         

2-1-6-1-3.کاربردهای درمانی مهار کنندگان غیر انتخابی آنزیم سیکلو اکسیژناز......................................43

 2-1-6-1-3-1. فعالیت  ضد التهابی داروهای ضد التهاب غیر استروئی...................................................... 43

2-1-6-1-3-2.اثرات ضد تب داروهای ضد التهاب غیر استروئیدی................................................................ 44

2-1-6-1-3.عوارض جانبی مهار کنندگان غیر انتخابی آنزیم سیکلو اکسیژناز............................................. 44

2-1-6-1-4-1. عوارض گوارشی............................................................................................................................. 45

2-1-6-1-4-2. عوارض پوستی :............................................................................................................................ 47

2-1-6-1-4-3. عوارض کلیوی :............................................................................................................................. 47

2-1-6-1-4-4. عوارض کبدی :.............................................................................................................................. 48

2-1-6-1-4-5. اثرات داروهای ضد التهاب غیر استروئیدی بر پلاکت ها...................................................... 48

2-1-6-1-4-6. واکنش حساسیت به نور:............................................................................................................   48

2-1-6-2. مهارکننده های انتخابی COX2 ......................................................................................................  48

2-1-6-2-1. طبقه‌بندی ساختمانی مهار کنندگان انتخابی cox-2 .............................................................  49

2-1-7. مسیر لیپوکسیژناز........................................................................................................................................ 50

2-1-8-1.  لکوترین‌ها..............................................................................................................................................  50

2-1-7-1-1. بیوسنتز...............................................................................................................................................  51

2-1-7-1-2. اثرات بیولوژیک لکوترین‌ها.............................................................................................................  54

2-1-7-1-3. اثرات لکوترین‌ها در فرآیند التهاب...............................................................................................  55

2-1-7-2. مهارکننده‌های لکوترینها:.....................................................................................................................  56

2-1-7-2-1. آنتی‌اکسیدانها:...................................................................................................................................  56

2-1-7-2-2. شلات کننده‌های آهن:....................................................................................................................  57

2-1-7-2-3. مهار کننده‌های رقابتی:...................................................................................................................  58

...............................................................................................................  59FLAP. مهارکننده‌های   2-1-7-2-4

2-1-7-2-5. آنتاگونیست رسپتور لکوترین‌ها:....................................................................................................  60

2-1-8. مسیرهاغیر آنزیماتیک...............................................................................................................................  61

2-1-8-1. مسیر ایزوپروستان.................................................................................................................................  61

2-1-8-2. مالون دی آلدهید...................................................................................................................................  64

2-1-8-4.3 هیدروکسی نوننال 4-Hydroxynonenal   ..........................................................................  65

2-1-8-4. نقش سوپراکسید و نیتریک اکسید در فرآیندهای التهابی...........................................................  66

بخش دوم:مطالعات دیگران دراین زمینه

2-2-1. بررسی مطالعات دیگران در این زمینه.................................................................................................... 70

2-2-2. مهار کننده‌های همزمان COX/LOX :............................................................................................  71

2-2-2-1.NSAID ‌های اصلاح شده: ...............................................................................................................  71

2-2-2-2. مشتقات ان-آریل فتالیمیدها:................................................................................................................71

فصل سوم: مواد وروش‌ها

3-3.مراحل فارماکولوژیک......................................................................................................................................... 76

3-3-1.حیوانات..........................................................................................................................................................  76

3-3-2.تهیه‌ی نمونه‌ها جهت انجام تست‌های فارماکولوژیک...........................................................................  76

3-3-3.اثرات ضد التهابی..........................................................................................................................................  77

3-3-5.انالیز اماری داده ها.........................................................................................................................................78

فصل چهارم: نتایج

فصل پنجم: بحث و نتیجه‌گیری

بحث و نتیجه گیری................................................................................................................................................  94

خلاصه انگلیسی.......................................................................................................................................................99 منابع..........................................................................................................................................................................

ندارد.

منبع:

Fiorucci S, Meli R, Bucci M. Dual inhibitors of cyclooxygenase and 5–lipoxygenase. A new avenue in anti-inflammatory therapy? Biochem. Pharmacol. 2001; 62 (11): p. 1433-1438

2) Garavito R.M. The cyclooxygenase-2 structure: new drugs for an old target? Nat. Struct. Biol. 1996;3 (11):p.897-901

3)Fosslien E.Adverse effects of  nonsteroidal anti-inflammatory drugs on the gastrointestinal system.Ann. Clin. Lab. Sci.1998;28 (2):p. 67-81

4)Hallas J,[et al]. Nonsteroidal anti-inflammatory drugs and upper gastrointestinal bleeding, identifying high-risk groups by excess risk estimates. Scand J Gastroenterol. 1995; 30: p .438-444

5)Warner TD,Mitchell J.A.Cyclooxygenase-3:Filling in the gaps toward a COX continuum. Proc. Natl. Acad. Sci.2002; 99:p.13371-13373

6) Pairet M, Ryn JV. COX-2 inhibitors. In: Milestones in Drug Therapy. First edition. 2004.p. 1-14

7) Dannhardt G, Keifer W. Cyclooxygenase inhibitors: current status and future prospects. Eur. J. Med. Chem. 2001; 36:p.109-126

8) Gilory DW, Tomlinson A, Willoughby DA. Cyclooxygenase may contribute to the resolution of inflammation. Eur. J. phrmacol. 1998; 355:p.211-217

9) Scott G. Stewart, Marta E. Polomska,anti inflammatory a new analog thalidomide.2002; 28:p.2375-2382

10) Foegh ML, Ramwell PW. The eicosanoids:prostaglandins,thromboxanes, leukotrienes, and related compounds.Frust DE, Munster T. Nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, nonopioid analgesics and drugs used in gout. In: Katzung, Basic & Clinical Pharmacology.New York: McGraw-Hill;2001 .pp.311-325 , 596-623

11) Gelott F, Laufer S. Anti- inflammatory drugs: New multitarget compounds to face an old problem. The dual inhibition concept. Pharmacol. Res. 2001;43:429-436

12) Funk CD. Prostaglandins and Leukotrienes: Advances in Eicosanoid Biology. Science. 2001; 294 (5548):p.1871-1875

13) Nies AS, Gresser M. J. Cyclooxygenase-2 inhibitors. Adv. Pro. Chem. 2001;56, p.115-141

14) Borne RF. Nonsteroidal anti-inflammatory agents. In: Williams DA.LemkeTL, Foye’s Principal of Medicinal Chemistry. Philadelphia: Lippincott Williams & Wilkins; 2002.p. 751-793

15) Roberts LJ, MorrowJ D. Analgesic-antipyretic and anti-inflammatory agentand drug employed in the treatment of gout. In: Hardman, LG. Limbird, LE. Goodman Gilman, A. eds. Goodman & Gilman’s pharmacological Basis Of Therapeutics. New York: McGraw-Hill; 2001.p. 687-731

16) Dannhardt G, LauferS. Structural approaches to explain the selectivity of COX-2 inhibitors.Curr.Med.Chem.2000;7:p.1101-1112

17) Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for Aspirin-Like drugs. Nature.1971; 231: 232-235

18) Fu JY,[et al].The induction and suppression of prostaglandine H2 synthase (cyclooxygenase) in human monocytes.J.Biol.Chem.1990;265:p. 16737-16740

19) Ristimaki A , Narko K, Hla T. Down- regulation of cytokine- induced cyclooxygenase-2 transcript isofroms by dexamethasone: evidence posttranslational regulation. Biochem. J. 1996;318:p. 325-331

20)Griag CR, Stitzel RE. Modern Pharmacology. 3 rd ed. London: Little and Brown company, Boston; 1990. PP . 509,517,521-522

21)Bowman WC, Rand MJ. Text book of pharmacology. 2 rd ed. Oxford:Black Well Scientific publication; 1980. PP. 5-6, 10-21

22) Rang HD, Dale MM. Pharmacology. Edinburg: Churchill living stone; 1987.pp.61-64, 451-453, 556-557 , 588

23) Sanderson JB. A system of surgery.2 rd ed. Longmans: Green and co; 1871.p.121

24) Spector WG, Willoughby DA. The inflammatory response. Bacteriological revieus. 1963;27:p. 117-149

25) Marks F.Arachidonic acid and companions: an abundant source of  biological signals. In: Marks F , Furstenberger G. Prostaglandins , leukotrienes and other eicosanoids: from biogenesis to clinical application. Weinheim: Wiley-VCH;1999.P.1-46

26)  Vane JR. Towards a better aspirin.Nature.1994;367:215-216

27) Kuhn H. Lipoxygenases. In Marks F, Furstenberger G.Prostaglandins,leukotrienes and othereicosanoids:from biogenesis to clinical application.Weinheim:Wiley-VCH;1999.P.109-142

28) Oliw EH,Ericsson J. Oxygenation of arachidonic acid by cytochromes P-450 In Marks F, Furstenberger G. Prostaglandins, leukotrienes and other  eicosanoids:from biogenesis to clinical application. Weinheim: Wiley-VCH;1999.P.143-168

29)HemlerM,LandsWE.Purification cyclooxygenase.J.Biol.Chem J.Biol.Chem1976;251(18)  :p .5575-5579.  .                        .

30) Dewitt DL, Smith WL. Primary structure of prostaglandin G/H synthase from sheep vesicular gland determined from the complementary DNA sequwnce. Proc. Natr. Acad.sci. U.S.A. 1988;85:p. 1412-1416

31) Xie W, Robertson DL, Simmons DL. Mitogen-Inducible Prostaglandin G/H Synthase: A New Target for Nonsteroidal Antiinflammatory Drug Develop.Res.1992;25:p. 249

32) Marnett L J, Rowlinson S W, Goodwin D C. Arachidonic Acid Oxygenationby COX-1 and COX-2 mechanisms of catalysis and inhibition. J.Biol. Chem.1999; 274 (33): p. 22903-22906

33) Dubois RN, [ et al]. Cyclooxygenase in biology and disease FASEB J. 1998; 12 (12):p. 1063–1073

34) Thomas J, Holmes JR. Prostaglandins, leukotrienes and other eicosanoids. In: Block, JR. Beale, JM. eds.Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry. Philadelphia: Lippincott Williams & Wilkins; 2004.p. 818-829

35)Hirai H, [et al]. Prostaglandin D2 selectivity induces chemotaxis in T helper type 2 cells,eosinophils.J.EXP.Med.2001;193:p. 255-261

36) Abramovitz M, Metters KM.Prostanoid receptors. Ann.Rep.Med.Chem. 1998;33:p. 223-231

37) Smith WL, Marnett LJ. Prostaglandin endoperoxide synthase: Structure and catalysis. Biochim. Biophys. Acta 1991;1083 (1):p. 1-17

38) Griswold DE,  Adams JL. Constitutive cyclooxygenase (COX-1) andinducible cyclooxygenase (COX-2): rationale for selective inhibition and progress to date. Med. Res. Rev.1996;16 (2):p. 181–207

39) Narumiya S, Sugimoto Y, Ushikubi F. Prostanoid receptors: structure, properties, and functions. Physiol.Rev. 1999;79:p. 1193-1226

40) Vane JR,Bakhle YS,  Botting RM. Cyclooxygenasesa1 and2. Annu. Rev.Pharmacol. Toxicol. 1998; 38:p. 97–120

41) Karman S,[et al].Characterization of prostaglandin G/H synthase 1 and 2 in rat, dog, monkey and humangastrointestinal tracts. Gastroenterology.1996;111:p. 445-454

42) Katori M, Majima M. Cyclooxygenase-2: its rich diversity roles and possible  application of its selective inhibitors.inflamm Res.2000;49:367-392

43) Fitzgerald GA, Ptrono C. The coxibs, selective inhibitors of cyclooxygenase-2.N Eng J Med.2001;345:p. 433-442

44) Bennet P, Slater D. Cox-2 expression in labour. In: Van Jr, Botting R(Eds).Improved non –steroidal anti-inflammatory drugs. Cox-2 enzyme inhibitors.Boston: Kluwer Academic publishers;1996.p.167-188

45) Gibb W, Sun M. Localization of prostaglandin H synthase type 2 protein and mRNA in term human fatal memberanes and deciduas.J.Endocrinal.1996;150:p. 497-503

46) SamadTA, Sapirstein A, Woolf CJ. Prostanoids and pain – unraveling mechanisms Trends Mol; Med. 2002; 8 (8):p. 390–396

47) Dewitt DL. COX-2 selective inhibitors: The new super aspirins. Mole. Pharmacol. 1999;55: p. 625-631

48) Chandrasekharan NV , [et al].COX-3 , a cyclooxygenase-1 varient inhibited  by acetaminophen and other analgesic/ anti pyretic drugs : cloning , structure and exoression.Proc.Natl.Acad.Sci.USA.2002;99: p. 13926-13931

49)Tazawa R,[et al]. Characterization of the genomic structure, chromosomal location and Biophys. Commun.1994;203:p. 190-199

50) Kosaka T, [et al]. Characterization of  human gene (PTGS2) encoding prostaglandin endoperoxide synthase-2.Eur.J.Biochem.1994;221: p. 889-897

51) Yokoyama C, Tanabe T.Cloning of human gene encoding prostaglandin endoperoxide

synthase and primary structure of the enzyme.Biochem.Biophys.Res.Commun.1989;165: p. 888-894

52) Kraemer SA, Meade EA, Dewitt DL . Prostaglandin  endoperoxide  synthase gene structure: Identification of  the  transcriptional start site and 5’-flanking  regulatory sequences. Arch.Biochem.Biophys.1992;293:p. 391-400

53) Rouzer CA, Marnett LJ. Mechanism of free radical oxygenation of Polyunsaturated fatty acids by cyclooxygenases. Chem .Rev. 2003;103: p. 2239-2304

54) Picot D. Loll PJ, Garavito RM.The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1.Nature.1994;367:p. 243-249

55) Mancini JA,Riendeau D,Falgueyret JP,Vickers PJ, O’Neill GP. Arginine 120 of prostaglandin G/H synthase-1 is required for the inhibition by nonsteroidal anti-inflammatory drugs containing a carboxylic acid moiety.J.Biol.Chem.1995;270: p. 29372-29377

56) Kurumbail RG, [et al]. Structural basis for selective inhibition of cyclooxygenase-2 by anti inflammatory agents.Nature.1996;384: p. 644-648

57) OuelletM, Percival MD. Effect of inhibitor time–depending on selectivitytowards cyclooxygenase isoforms. Biochem. J. 1995;306:p. 247-251

58) Brooks DM, Day RO. Nonsteroidal anti–inflammatory differences and similarities. N. Engl. J. Med.1991; 324:p. 1716–1725

59) Brandt KD. Hypertrophic repair of canine articular cartilage in osteoarthritis after anterior cruciate ligament transaction. J.Rheumatol.1991;18: p. 120-121

60) Bron RF. Nonsteroidal anti–inflammatory agents. In: Williams DA. Lemeke L. Foye’s principle of medicinal chemistry. Philadelphia: Lippincott Williams & Wilkins; 2001.P. 411

61) Moor DE.Nonsteroidal anti inflammatory drugs.Drug Safety.2002;25(5):p. 345

62) Bell RL,  Harris RR, n Stewat, A.D. Cox-2 inhibitors and leuko triene modulators. In: Abraham, D.J., ed. Burger’s Medicinal Chemistry and Durg Discovery. New Yersy: John Wiley.2003; 4:p. 203–263