chemistry of prostaglandins & leukotrienes

1. CHEMISTRY OF
PROSTAGLANDINS &
LEUKOTRIENES
Presented by:
Tathagata Pradhan
M.Pharm (Chemistry)
Presented to:
Dr. Vikram Deep
Monga

2. History
• IN 1930, Kurzok & Lieb American Gynaecologist observed
strips of human uterus relax or contract when exposed to
human semen.
• Few Years later, Von Euler (Sweden) ,Goldblast (England)
reported smooth muscles contracting & vasodepressor
activity in seminal fluid.
• The name prostaglandin derives from the prostate gland,
chosen when prostaglandin was first isolated from seminal
fluid in 1935 by the Swedish physiologist Ulf von Euler.
• PGE₁& PGF₁α structures were elucidated in 1962.

3. Introduction
• Prostaglandins (PG) and related compound prostacyclin (PGI),
thrombaxanes (TXA), leukotrienes (LT) & lipoxins are
collectively known as Eicosanoids, they all contain 20 carbon.
• PGs are derivative 20 carbon fatty acid-prostanoic acid, hence
known as prostanoids.It may have 3,4 or 5 double bonds.
• Arachidonate - most abundant precursor – derived from
dietary linoleic acid or injested as a dietary constituent. It is
esterified to the phospholipids of cell membrane or other
complex lipids.
• Biosynthesis of Eicosanaoids depends mainly upon the
availability of Arachidonate to Eicosanoids synthesizing
enzymes notably Phospholipase A₂.

5. Nomenclature of Prostaglandins
• Prostanoic acid (7-[(1S,2S)-2-octylcyclopentyl]heptanoic acid)
is a saturated fatty acid which contains a cyclopentane ring.
Its derivatives are prostaglandins - physiologically
active lipid substances.

8. Cyclo oxygenase Pathway

9. Conversion of Arachidonic acid to
PGG₂

10. Prostaglandin E₁ (PGE₁)

12. Prostaglandin D₂ (PGD₂)

13. Prostaglandin F₂α (PGF₂α)

14. SAR of PGs
• In the upper chain : Methyl Esters (misoprostol) ,sulphonamide
(sulprostone) and hydroxyl group (rioprost) posses greater activity than
natural PGs.
• In the cyclopentane ring : Variation in the cyclopentane ring results in a
reduction in the PG activity. Enlargement of the ring or reduction of the
ring leads to inactive compounds. Replacement of the carbon atom of
cyclopentane ring by O, S, and N also leads to inactive compounds.
Replacement of 9-keto group with =CH2 group gives active (metenprost)
PG.
• In the lower chain : C-15 hydroxyl group is protected from metabolism by
the introduction of methyl group at C-15 and gem dimethyl group at C-16 .
The shifting of C-15 hydroxyl group to C-16 position increases the
metabolic stability of alkoxy, phenoxy analogues, and they are more active
than natural PGs.

15. Prostanoid Receptors
• PGs ,TX and prostacyclin act on their own specific receptors
located on cell membrane.
• Five families of prostanoid receptors(DP, EP, FP, IP, TP) have
been designated, each after the endogenous PG for which it
has the greatest affinity.
• All prostanoid receptors are G-protein coupled receptors
which can be functionally categorized into ‘contractile’,
‘relaxant’ and ‘inhibitory’ groups.

17. Function of PG

18. Uses
I. Abortion : PGs have a place in midterm abortion, missed
abortion. Methotrexate alongwith misoprostol is also highly
successful for inducing abortion in the first few weeks of
pregnancy. Pretreatment with mifepristone improves the efficacy
of PGE₂ as abortifacient.
II. Cervical priming : Applied Intravaginally or in the cervical canal,
low doses of PGE₂ which do not affect uterine motility, make the
cervix soft and compliant.
III. Glaucoma : Topical PGF₂α analogues like lanatoprost, bimatoprost
that are FP receptor agonists are the first choice drugs in wide
angle glaucoma.
IV. Peptic ulcer : PGE₁ (misoprostol) is occasionally used for healing
peptic ulcer.
V. Avoid Platelet damage : PGI₂ (Epoprostenol) can be used to
prevent platelet aggregation and damage during haemodialysis.
VI. Impotence : Alprostadil (PGE₁) injected into penis causes erection
lasting 1-2 hrs.

20. Leukotrienes
• Leukotrienes (LTs) are so named because they
were first obtained from leukocytes and have
3 conjugated double bonds (triene). They have
also been similarly designated A,B,C……F and
given subscripts 1,2,3,4.

21. LEUKOTRIENE A₄

22. Lipo oxygenase Pathway

23. Leukotrienes Receptors
• Separate receptors for LTB₄(BLT₁ and BLT₂) and for the
cysteinyl LTs (LTC₄,LTD₄) have been defined. Two subtypes,
cysLT₁ and cysLT₂ of the cysteinyl LT receptor have been
cloned.
• All LT receptors couple with Gq protein and function through
the IP₃/DAG transducer mechanism. The BLT receptors are
chemotactic and primarily expressed in leukocytes and
spleen. BLT₁ receptor has high affinity while BLT₂ receptor has
lower affinity for LTB₄.
• The cysLT₁ receptor is mainly expressed in bronchial and
intestinal muscle and has higher affinity for LTD₄ than for
LTC₄.The cysLT₁ receptor antagonists i.e. Montelukast,
Zafirlukast are now valuable drugs for bronchial asthma.

24. Functions
• Leukotrienes act principally on a subfamily of G protein-
coupled receptors. Leukotrienes are involved in asthmatic
and allergic reactions and act to sustain inflammatory
reactions. Several leukotriene receptor antagonists such
as montelukast and zafirlukast are used to treat asthma.
Recent research points to a role of 5-lipoxygenase in
cardiovascular and neuropsychiatric illnesses.
• Leukotrienes are very important agents in
the inflammatory response. Some such as LTB4 have
a chemotactic effect on migrating neutrophils, and as such
help to bring the necessary cells to the tissue. Leukotrienes
also have a powerful effect in bronchoconstriction and
increase vascular permeability

26. Structures of Anti Leukotrienes