5 - Leukotrienes Flashcards
What are corticosteroids used for w/ respect to asthma?
To control the underlying inflammatory disease
What can overuse of corticosteroids result in?
- Weight gain, edema
- Gastritis
- Hypertension
- CNS disorders
- Glaucoma
- Hyperglycemia
- Osteoporosis
Why are leukotrienes are target for asthma therapy?
Release of leukotrienes in lungs results in bronchoconstriction and excessive mucous production
How are leukotrienes produced?
Arachidonic acid -> 5-HPETE -> LTA4 -> leukotrienes
Are the double bonds of arachidonic acid in conjugation?
No
What makes 5-HPETE and LTA4 more thermodynamically favourable than arachidonic acid?
- 5-HPETE has 2 double bonds in conjugation
- LTA4 has 3 double bonds in conjugation
What is zileuton?
5-lipoxygenase inhibitor, so prevents formation of leukotriene A4
Which leukotrienes are agonists for the CysLT1 receptor? What does their binding cause?
- Leukotriene C4, D4, and E4
- Binding causes smooth muscle constriction, eosinophil migration, and edema
Which drugs are antagonists of the CysLT1 receptor?
- Montelukast
- Pranlukast (not available in Canada)
- Zafirlukast
Where is leukotriene B4 released in the body? What is its function?
- Released elsewhere in the body other than bronchi
- Attracts monocytes from blood to sites of cell injury, undergoing cellular differentiation to produce macrophages, the main inflammatory mediator
How are LTC4 and LTD4 produced?
- LTC4 synthase facilitates addition of glutathione to C6 of LTA4, producing LTC4
- LTD4 is produced through cleavage of gamma-glutamic acid residue on LTC4 via gamma-glutamyl transpeptidase
What is LTC4 synthase also referred to as?
Glutathione S-transferase 2
Which part of LTD4 is ionized when it binds to the active site of the CysLT1 receptor?
Only one carboxylic acid group (normally the one in the hydrophilic pocket)
Which mediators are released during allergic rhinitis?
Histamines, prostaglandins, and leukotrienes
Do montelukast (leukotriene antagonist) and antihistamines produce a synergistic or antagonistic effect when dosed in combination?
Synergistic
What is important about the structure of zafirlukast?
Benzylic carbon will metabolize to a carboxylic acid, making this compound a prodrug
Leukotriene B4 is involved in ______ and binds to the _____ receptor
Chemotaxis; BLT receptor
What happens after leukotriene B4 binds to the BLT receptor?
Induces activation of leukocytes and, in neutrophils, induces formation of reactive oxygen species and release of lysozymes
What are benefits to injections of LTB4?
- Beneficial against transplant rejection and opportunistic infections
- Produce anti-HIV mediators
- Fight bacteria and elicit antiviral responses
How is leukotriene B4 produced?
Leukotriene A4 is hydrolyzed by leukotriene A4 hydrolase to produce leukotriene B4
Does leukotriene B4 produce any active metabolites?
No, only inactive (dramatically less potent)
What must be prevented to make stable analogues of leukotriene B4?
- w-tail oxidation
- C-12 oxidation
- Double bond reduction
What can be done to prevent oxidation of C-12 of leukotriene B4?
- Conversion of secondary alcohol to a tertiary alcohol
- Beta substitution of fluorines for hydrogens at C-13
To block oxidation at a carbon, replace _____ with _____
Hydrogens w/ fluorines
What can be done to the structure of LTB4 to produce an antagonist?
- Desaturation of C-14 and C-15 (alkyne)
- Replacement of w-tail w/ cyclohexylethyl or cyclohexyl
Which atoms can be in the stereospecific site of a molecule that binds to the CysLT receptor?
N, O, or S
