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Medicinal Chemistry - Winter > 5 - Leukotrienes > Flashcards

5 - Leukotrienes Flashcards

1
Q

What are corticosteroids used for w/ respect to asthma?

A

To control the underlying inflammatory disease

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2
Q

What can overuse of corticosteroids result in?

A
  • Weight gain, edema
  • Gastritis
  • Hypertension
  • CNS disorders
  • Glaucoma
  • Hyperglycemia
  • Osteoporosis
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3
Q

Why are leukotrienes are target for asthma therapy?

A

Release of leukotrienes in lungs results in bronchoconstriction and excessive mucous production

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4
Q

How are leukotrienes produced?

A

Arachidonic acid -> 5-HPETE -> LTA4 -> leukotrienes

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5
Q

Are the double bonds of arachidonic acid in conjugation?

A

No

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6
Q

What makes 5-HPETE and LTA4 more thermodynamically favourable than arachidonic acid?

A
  • 5-HPETE has 2 double bonds in conjugation

- LTA4 has 3 double bonds in conjugation

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7
Q

What is zileuton?

A

5-lipoxygenase inhibitor, so prevents formation of leukotriene A4

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8
Q

Which leukotrienes are agonists for the CysLT1 receptor? What does their binding cause?

A
  • Leukotriene C4, D4, and E4

- Binding causes smooth muscle constriction, eosinophil migration, and edema

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9
Q

Which drugs are antagonists of the CysLT1 receptor?

A
  • Montelukast
  • Pranlukast (not available in Canada)
  • Zafirlukast
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10
Q

Where is leukotriene B4 released in the body? What is its function?

A
  • 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
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11
Q

How are LTC4 and LTD4 produced?

A
  • 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
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12
Q

What is LTC4 synthase also referred to as?

A

Glutathione S-transferase 2

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13
Q

Which part of LTD4 is ionized when it binds to the active site of the CysLT1 receptor?

A

Only one carboxylic acid group (normally the one in the hydrophilic pocket)

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14
Q

Which mediators are released during allergic rhinitis?

A

Histamines, prostaglandins, and leukotrienes

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15
Q

Do montelukast (leukotriene antagonist) and antihistamines produce a synergistic or antagonistic effect when dosed in combination?

A

Synergistic

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16
Q

What is important about the structure of zafirlukast?

A

Benzylic carbon will metabolize to a carboxylic acid, making this compound a prodrug

17
Q

Leukotriene B4 is involved in ______ and binds to the _____ receptor

A

Chemotaxis; BLT receptor

18
Q

What happens after leukotriene B4 binds to the BLT receptor?

A

Induces activation of leukocytes and, in neutrophils, induces formation of reactive oxygen species and release of lysozymes

19
Q

What are benefits to injections of LTB4?

A
  • Beneficial against transplant rejection and opportunistic infections
  • Produce anti-HIV mediators
  • Fight bacteria and elicit antiviral responses
20
Q

How is leukotriene B4 produced?

A

Leukotriene A4 is hydrolyzed by leukotriene A4 hydrolase to produce leukotriene B4

21
Q

Does leukotriene B4 produce any active metabolites?

A

No, only inactive (dramatically less potent)

22
Q

What must be prevented to make stable analogues of leukotriene B4?

A
  • w-tail oxidation
  • C-12 oxidation
  • Double bond reduction
23
Q

What can be done to prevent oxidation of C-12 of leukotriene B4?

A
  • Conversion of secondary alcohol to a tertiary alcohol

- Beta substitution of fluorines for hydrogens at C-13

24
Q

To block oxidation at a carbon, replace _____ with _____

A

Hydrogens w/ fluorines

25
Q

What can be done to the structure of LTB4 to produce an antagonist?

A
  • Desaturation of C-14 and C-15 (alkyne)

- Replacement of w-tail w/ cyclohexylethyl or cyclohexyl

26
Q

Which atoms can be in the stereospecific site of a molecule that binds to the CysLT receptor?

A

N, O, or S

Medicinal Chemistry - Winter (15 decks)

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