7.11 Eicosanoids, Fatty-Acid Nomenclature & Leukotriene Drugs – Comprehensive Exam Notes

Exam 3 & Final Logistics

• 3 lectures on eicosanoids & NSAIDs (including today) only on the Final, not Monday’s Exam 3

• Monday’s Exam 3:
  • $35$ graded questions
  • $+3$ remediation questions (worth $2$ pt each)
  • Formats: 2 fill-in-the-blank, 2 matching, rest multiple-choice

• Updated learning-objective handout:
  • Use pK$_{a}$ $\approx3$ for carboxylic acids
  • Use pK$_{a}$ $\approx9$ for amines

Key Terminology Refresher (fatty acids/eicosanoids)

• PUFA = Poly-Unsaturated Fatty Acid

• Unit of unsaturation: each double bond, triple bond, or ring adds one unit

• Omega numbering: count from the terminal (ω) carbon toward the carbonyl until 1st double-bond carbon is reached
  • Common dietary buzzwords: ω-3, ω-6 PUFAs

• cis vs trans:
  • Natural fatty acids almost exclusively cis; trans creates “kinks” and alters bio-function

Core PUFA Examples

Guideline to name:

1. Count carbons, write $C:n$

2. Count DBs (= n)

3. State ω-position (first DB from tail)

4. State cis/trans for each DB if mixture; “all cis” acceptable

Eicosanoids Overview

• Definition: Oxidized, 20-carbon, PUFA-derived signaling molecules

• Classes
  • Prostanoids (derived via COX): prostaglandins (PG), thromboxanes (TX), prostacyclins (PGI)
  • Leukotrienes (LT) & HPETEs (via LOX)
  • Epoxyeicosatrienoic acids (EETs) & HETEs (via P450 epoxygenase)

Mnemonic: “Membrane is the message” – synthesized on-demand from membrane phospholipids, act locally, rapidly degraded

Liberation of Arachidonic Acid (AA)

1. Phospholipase A₂ (PLA₂)
   • Clips sn-2 fatty acid of phospholipids (often AA)
   • Activated by trauma/inflammation; inhibited by steroids

2. MAG-lipase (MAGL) pathway
   • Phospholipase C → Diacylglycerol (DAG)
   • DAG-lipase → 2-Arachidonoylglycerol (2-AG)
   • MAGL hydrolyzes 2-AG → AA $+$ glycerol
   • In brain, $\approx80\%$ of AA comes from MAGL, not PLA₂
   • 2-AG = endocannabinoid, full agonist at CB₁/CB₂

Leukotriene Biosynthesis

AA --(5-LOX + FLAP)--> 5-HPETE → LTA₄ →
      |  (glutathione conjugation)
      ↓
.L;/,   LTC₄ → LTD₄ (–Glu) → LTE₄ (–Gly)

• 5-LOX = 5-Lipoxygenase; FLAP = 5-LOX-activating protein

• LTA₄ = epoxide intermediate (first true leukotriene)

• Cys-LTs (LTC₄, LTD₄, LTE₄) have cysteine moiety; major bronchoconstrictors in asthma

Glutathione & NAC

• Glutathione (GSH): $\gamma$-Glu-Cys-Gly tripeptide; chief cellular antioxidant

• Conjugated to LTC₄ via thio-ether (not disulfide)

• Clinically we cannot dose GSH (too polar); we give N-acetyl-L-cysteine (NAC)
  • NAC replenishes GSH; antidote for acetaminophen overdose
  • Tastes like “lemon-onion”; oral/IV forms

Leukotriene-Pathway Drugs ("Leukotriene Modifiers")

1. Synthesis Inhibitor (LOX / FLAP)

• Zileuton
  • Oral $q6h$; hydroxyl-urea + benzothiophene scaffold
  • Inhibits 5-LOX → ↓ Cys-LTs
  • Liver monitoring (rare hepatotoxicity)

2. CysLT₁-Receptor Antagonists

Design rationale (pre-GPCR crystal era):

• Modelled hydrophobic pockets + acidic “salt-bridge” mimic of LT carboxylate

Mast-Cell Degranulation Inhibitors (Chromones)

• Cromolyn sodium, Nedocromil

• Very hydrophilic (multiple –COOH); poor oral F; used inhaled/nasal

• pK$_{a}$ (COOH) $\approx3$ (rule-of-thumb)

• Must be given prophylactically before antigen exposure

Functional-Group & Ring Identification Cheatsheet

• Urea vs Hydroxyurea: $\mathrm{O=C(NH<em>2)</em>2}$ vs $\mathrm{O=C(NHOH)(NH_2)}$

• Carbamate: $\mathrm{O=C(OR)(NR_2)}$

• Sulfonamide: $\mathrm{SO_2NH}\text{-}$

• Indole = fused benzene + pyrrole

• Benzofuran / Benzothiophene analogs (O vs S)

• Thio-ether vs Disulfide: $\mathrm{R-S-R’}$ (one S) vs $\mathrm{R-S-S-R’}$ (two S)

Exam-Style Skill Reminders

• Be able to:
  • Count C:DB:ω and name any PUFA
  • Assign cis/trans or $E/Z$ for DBs
  • Recognize drug functional groups & estimate pK$_{a}$ ( COOH $\sim3$, amine $\sim9$ )
  • Distinguish prostanoids (contain rings) vs leukotrienes (no rings)
  • Map PLA₂ vs MAGL pathways

Practical / Clinical Connections

• Expect surge in lipid-targeting drugs over next 20 yrs (GPCR, P450, LOX, MAGL, DGAT, etc.)

• Steroids blunt inflammation partly by inhibiting PLA₂, upstream of all eicosanoids

• MAGL inhibitors (research) produce cannabinoid-like CNS effects (↑2-AG) and anti-inflammatory profile

• CysLT antagonists: add-on for asthma, aspirin-exacerbated respiratory disease (AERD), allergic rhinitis

Ethical / Practical Take-Home

• Knowing “one step more” chemistry makes you the go-to medication expert; keep learning attitude, verify references (textbooks can be wrong)

• Lipid pharmacology historically neglected due to lab handling challenges; new tech (robotics, GPCR crystallography) fueling breakthrough pace