Prostaglandins and Leukotrienes

Structure of Prostacyclin

Structure of PGE2

Structure of PGF2a

Structure of TXA2

Structure of PGD2

What groups do prostaglandins have?

1. Oxygenated cyclopentane/pentene ring

2. Heptenoic/heptanoic acid side chain

3. Octenol side chain

Are prostaglandin side chains cis or trans

Two side chains are trans to each other

Soft spots of Prostenoic acid?

What is thromboxane derived from? What membered ring does it have?

1. Derived from PGH2

2. Six membered ring

Soft spots of thromboxane (TXB2)

What are leukotrienes derived from? Which pathway do they follow? Do they have rings?

1. Derived from 5-HPETE

2. Lipoxygenase pathway

3. NO RINGS

4. Subscript: Number of double bonds

Where does LTC4 and LTD4 come from?

LTA4

What functional group does LTA4 contain? What does it mean in terms of activity?

1. Epoxide

2. Electrophilic (delta +) → thiols will open this

3. Opens, creates trans product

What is LTC4?

Glutathione (Trans)

What is LTD4?

Cysteine + Glycine

What is LTE4?

Cysteine

What are important points about LTC4-LTE4

1. Thiol epoxide trapping of LTA4

2. Leukotrienes → produced through 5-LPO on arachidonic acid

3. Epoxide ring → gives trans product

Which receptors does PGE2 bind to?

EP1, EP2, EP3, EP4

What receptors does PGF2a bind to?

FP receptors

What receptors does PGI2 bind to?

IP receptors

What receptor does TXA2 bind to?

TP alpha, beta

What receptors do PGD2 bind to?

DP1 and DP2

What receptors does LTB4 bind to?

LTB4R1 and LTB4R2

What receptors do LTC4, LTD4, and LTE4 bind to?

CysLTR1 and CysLTR2

Biological functions of PGD2

Mast cell maturation, vasodilation, neuroprotection

Biological functions of PGE2

Vasodilation, labor induction

Biological functions of PGF2a

Uterine, vascular, respiratory contraction, decrease of intraocular pressure

Biological functions of PGI2

Decrease platelet aggregation and vasodilation

Biological function of TXA2

Increased platelet aggregation, vasoconstriction, decrease T cell activity

Biological functions of LTC/D4

Bronchoconstriction, vascular leakage, neutrophil extravasation

How many double bonds does PGE1 have? What is it used to treat? What is its metabolism?

1. one double bond

2. infants with ductal dependent congenital heart disease

3. 80% is metabolized in one pass through beta/omega oxidation

Where is the soft spot of iloprost?

How does iloprost compare to prostacyclin PGI2

iloprost = primarily beta oxidation (has acetylene), E vs Z

Soft spots of latanoprost?

Is latanoprost a prodrug, what is the primary metabolism?

1. Yes, it is a prodrug

2. Hydrolyzed by esterases

3. Primarily metabolized via fatty acid beta oxidation

4. FP receptor

Misoprostol soft spots?

has 1 double bond

How quickly is misoprostol absorbed? Which metabolism is blocked?

1. Rapidly absorbed, peak 30 mins (pro drug)

2. Metabolism of 15-hydroxy blocked by 15-methyl group

What is the Singulair / LTD4 pharmacophore? Metabolism?

Hydrophobe, Acid, Hydrophilic

CYP2C8 - heavy metabolism

What heterocycle is in singulair?

Quinoline