(19) Muscarinic Antagonists

AGONIST vs ANTAGONIST MAIN SAR DIFFERENCE!

• ANTAGONISTS ARE BIGGER.

• Agonist → small/compact

• How professor wants you to recognize ANTAGONIST:

  • Find the nitrogen
    → look underneath/around it
    → see a large saturated cycloaliphatic ring

    → think muscarinic antagonist

Antagonist SAR - topic overview

• AMINE

• LINKER

• ESTER region

• R1 + R2

• R3

SAR

AMINE

1. Same as agonist:

   1. Quatienry N

      1. always ionized - binding (highest muscarinic activity)

   2. Tertiary Amine

      1. ionized - binding

      2. unionized - skin/cns penetration

2. NEW: What makes it angnost is N can have groups attached:

   1. optimal groups are the ones who allow binding to happen (more potent):

      1. methyl + methyl

      2. methyl + H

3. NEW: When looking at the groups on N outside the large ring:

   • Up to 4 carbons → max/survives

   • 5 or more carbons → inactive

SAR

LINKER

• Longer/bulkier linker → antagonist behavior

• Antagonists do NOT have to obey Ing's Rule of 5.

SAR

ESTER REGION

• Ester = optimal activity

• BUT unlike agonists, antagonists can also tolerate:

  • ether

  • even no heteroatom

  • Why?

    • Other bulky parts of the antagonist make enough receptor interactions to compensate.

• Why isn't the antagonist ester hydrolyzed immediately?

  • Antagonist ester → protected by bulky structure

    • → esterase has difficulty reaching ester
      → less rapid hydrolysis

SAR

ESTER REGION - draw me different regions

R1 + R2

• R1 and R2 should generally be rings.

• R and S = equally active

• Potency rule

  • 1 ring = good

  • 2 identical rings = better

  • 2 different rings = BEST

    • 1 saturated + 1 unsaturated/aromatic ring

  • fused ring = too bulky/inactive

R3

• R3 can commonly be:

  • H = lower potency

  • OH/CH₂OH = better potency

    • → H-bond with Asparagine (Asn)
      → stronger interaction → ↑ potency

• 
  

R3 - draw

Patch rule

• Patch → needs free-base / uncharged form to cross skin

  • Therefore: Quaternary ammonium → cannot be a patch

ANTAGONIST Drugs

• Oxybutynin: (ADD YELLOW INFO)

  • Alkyne replaces bulky cycloaliphatic region:

    • less lipophilic
      → ↑ aqueous solubility
      → ↑ oral bioavailability

  • 2 different rings + O-R3 help potency, while N bulk works against it

  • “All Smart Interns Take Orders.”

Atropine - draw

Scopolamine - patch

Ipratropium - draw

Tiotropium - draw

Oxybutynin - draw

Muscarinic structure fast cehck (REVIEW TO MYSELF)

N
→ tertiary or quaternary? - PENETRATION OR NO
→ small or crowded? - POTENCY

R1/R2
→ 1 ring, 2 same, or 2 different? - POTENCY

R3
→ oxygen present? - POTENCY