Title: Prostaglandins
1Prostaglandins NSAIDs
- Cheryl Tajon
- October 13, 2008
- Review Session Exam 1
- Walter Holleran
2Formation of Eicosanoids
1 pathway
Lehninger Principles of Biochemistry, 3rd
Edition, Nelson, D. and Cox, M., p.378
3Formation of Eicosanoids
1 pathway
C204 or 204?5, 8, 11, 14
Lehninger Principles of Biochemistry, 3rd
Edition, Nelson, D. and Cox, M., p.378
49
12
Essential fatty acids (EFAs)
5Cyclooxygenase (COX) mechanism
COX-2 PDB 6COX
6Cyclooxygenase (COX) mechanism
COX-2 PDB 6COX
7(No Transcript)
81 unsaturated bond
Saturated
I
91 unsaturated bond
Saturated
Bridged bicyclic system
Bridged bicyclic system
I
2 fused rings
10?-3 FAs (like PGE3) are generated from
eicosapentaenoic acid.
11- Synthetic PGE1 analogue
- Prevents NSAID-induced ulcers
- C16 methyl increases stability and half-life
- Treats impotence
- Given as an injection or urethral suppository
- PGI2 analogue
- Treats hypertension
- Disadvantage requires
- a central line
- Short half-life (3-5 min)
- Induces uterine contractions
- Prepares cervix for labor delivery
- Induces abortion (1st 2nd trimester)
12 13Arachidonic acid
COX
Present in blood platelets
Thromboxanes induce constriction of blood vessels
and platelet aggregation (blood clotting). Low
doses of aspirin, taken regularly, reduce the
probability of heart attacks and
strokes. Lehningher Principles of Biochemistry,
3rd Ed., p.785
14 15COX cyclic pathway Lipoxygenase linear
pathway found in leukocytes incorporates
molecular oxygen into arachidonate
(5-hydroperoxyeicosatetraenoate)
Chemoattractant for neutrophils
16Arachidonic acid
lipoxygenase
17What conditions are NSAIDs used?
- 1o treat inflammation, mild to moderate pain,
fever - Specific uses headaches, arthritis, sports
injuries, menstrual cramps - Included in cold/allergy preparations
18Molecular target for NSAIDs
- COX is a homodimer.
- Active sites for COX1 2 are different.
- COX2 has an extended binding pocket that can be
utilized for selectivity. - All COX inhibitors, regardless of selectivity,
bind in the arachidonic acid binding site.
TiPS Nov 1999 (vol. 20)
19Prototype NSAIDs
- Inhibits by acetylating a serine residue in the
active site.
- However, NSAIDs can also inhibit synthesis of
beneficial prostaglandins in GI tract and kidney.
20Critical single carbon bridge
- Ibuprofen
- (S) is the active enantiomer.
- Less potent, more liver toxicity w/o -CH3 group
acid
21Aryl Propionic Acids
naphthalene
isobutyl
22Indole Acids
23(No Transcript)
24COX has two isozymes.
- Both carry out the same reactions, but
COX-1 Active under normal healthy conditions
COX-2 Normally dormant when activated produces
excess inflammatory prostaglandins
Selective COX-2 inhibitors
25Flurbiprofen
DuP 697
26General structure for COX2 Selective NSAIDs
- Consist of a central ring with 1,2-biaryl
substitution
27(No Transcript)
28(No Transcript)
29Acetaminophen Toxicity
30Leukotriene Synthesis
- Targeting FLAP will inhibit 5-lipoxygenase
31- Inhibits synthesis of leukotrienes
- Approved 10yrs ago for asthma
32Arachidonic acid
lipoxygenase
33- Recently approved
- Less effective than steroids
34- Present at physiological pH.
- Develop antagonists of this species against H1
receptor.
35Usually methyl, but not always
Basic N
Linker variability in X Y
1st generation antihistamines crossed blood-brain
barrier.
36(No Transcript)
37Basic N
- Weakly or non-sedating
- Dont cross blood-brain barrier
- Both compounds are metabolized by Cyt P450.
X
38- Active drug
- Not converted in the reverse fashion
39All are competitive and bind with increased
affinity for TNFa.
Humira
Remicade
Enbrel
40Important in gout used in combination with
methotrexate.
Purpose to reduce binding of leukocytes to the
endothelium
41(No Transcript)