(18) Muscarinic Agonists

Muscarinic receptors

• Muscarinic receptors are GPCRs.

• There are M1–M5 receptors, located throughout the body.

Muscarinic receptors - main idea

• Because muscarinic receptors are widespread: (drug activates/blocks muscarinic receptors)

  • effects can happen in multiple organs

  • heart + GI + glands + eyes can all be affected.

• muscarinic receptors bind to acetylcholine

  • acetylcholine (ACh) is endogenous, meaning your body naturally makes it, and neurotransmitter.

Agonist vs Antagonist Effects

System	Agonist	Antagonist
Heart	↓ HR, ↓ cardiac output	↑ HR
GI	↑ smooth-muscle contraction	↓ contraction (constipation/urinary retention)
Glands	↑ sweating, lacrimation, salivation	↓ gastric/mucociliary/salivary secretions (dry mouth)
Eye	Pupil constriction	Pupil dilation (blurry vision)

Easy memory

Agonist = squeeze + secrete (GI/GLAND)

Antagonist = relax + dry (GI/GLAND)

THERAPEUTIC APPLICATIONS (what the drugs are used for.)

Agonists

• Miosis for eye surgery

• Lower intraocular pressure

• Glaucoma

• Promote urination

Antagonists

• Bradycardia

• Prevent nausea/vomiting

  • motion sickness

  • post-operative

• Control respiratory secretions

• COPD

Clinical class difference

Antagonists
→ larger/more clinically relevant class
→ better oral bioavailability

Agonists
→ generally require more local delivery

Define

Pharmacophore

3D arrangement of the minimum features/interactions required for binding.

MUSCARINIC AGONIST PHARMACOPHORE

• Ionized amine

• H-bond acceptor

• Ing's Rule of 5

MUSCARINIC AGONIST PHARMACOPHORE (draw it)

Ionized amine

• Acetylcholine has a quaternary ammonium → already positively charged.

  • The ionized/cationic amine is required for binding.

• most essential pharmacophore component because it participates in several important receptor interactions.

• anchors drug in receptor

Quick refresher:

quaternary ammonium: nitrogen has FOUR carbon attachments → N⁺

H-bond acceptor

• either ester oxygen can serve as the acceptor.

ING'S RULE OF 5

• For muscarinic AGONISTS only!

• counting rule

  • Start at the cationic nitrogen

  • count through the structure

  • count heavy atoms only (non-hydrogen atoms.)

HOW ACh BINDS THE MUSCARINIC RECEPTOR? - topic overview

• MOST IMPORTANT — Ion-ion interaction

• Pi-cation interaction

• Hydrogen bond

Ion-ion interaction

ACh positive amine + negative Asp negative → ion-ion bond

Pi-cation interaction

ACh positive amine + Tyr π electrons in aromatic → pi-cation interaction (3)

Hydrogen bond

ACh ester + Tyr phenol (hydrogen-bond donor) = H-bond

 Acetylcholine problems

• Nonselective

  • Acetylcholine activates: Muscarinic receptors + nicotinic receptors

    • → off-target activity

• Ester is unstable → rapidly hydrolyzed by esterases

  • very short DOA

  • It’s also acid labile

    • acidic stomach → ester hydrolysis and poor oral use

• Quaternary ammonium (permanently positively charged) → poor membrane penetration

  • BUT: excellent water solubility

The 3 agonist SAR regions

AMINE — LINKER — ESTER

agonist SAR

AMINE

• Quaternary ammonium — most active

  • Always ionized (+)

  • Positive charge → strong muscarinic receptor binding

  • Poor membrane/BBB penetration

• Tertiary amine (at least 2 methyl groups attached to N) — can still have useful agonist activity

  • Ionized/protonated (+) form → muscarinic receptor binding/activity

  • Un-ionized/neutral form → better skin/membrane/brain penetration

• Groups attached to N

  • Small groups → favors agonist

  • Larger/bulkier groups → shifts toward antagonist activity

agonist SAR

LINKER

• α-methylation: ↓ muscarinic activity

  • adds steric bulk →disrupts Asp ion-ion interaction

• β-methylation: better muscarinic selectivity

  • strengthens the interaction involving the ester oxygen + Tyr

  • adds some steric protection from esterases;

    • β-methyl stereochemistry: S (Strong)

      • S isomer = active / equipotent to acetylcholine

      • R isomer = ~20-fold reduction in activity

• Ing's Rule of 5

  • Make the structure too long/bulky → lose agonist character and move toward antagonism

agonist SAR

Ester

• Regular ester

  • esterase hydrolysis: short duration

• Fix: ester → carbamate

  • resonance stabilization

  • harder to hydrolyze: longer duration of action

REVIEW: MOST IMPORTANT AGONIST DISTINCTION

β-METHYL = SELECTIVITY

CARBAMATE = DURATION

AGONIST DRUG CHART

• Methacholine: S isomer = active

Methacholine - draw

Carbachol - draw

Bethanechol - draw

Pilocarpine - tell me more

Structure

• Has a lactone

  • lactone = cyclic ester

  • hydrolysis

  • epimerization (R form is less active)

• Has an imidazole instead of quaternary ammonium

  • Has ionized and unionized form

    • ionized - binding (does not follow normal SAR rule)

    • unionized - CNS penetration

• does not follow normal SAR

Pilocarpine - draw