Neostigmine

• Neostigmine is a synthetic quaternary ammonium compound that acts as a reversible cholinesterase inhibitor.
• It inhibits the enzyme acetylcholinesterase, thereby increasing the concentration of acetylcholine at neuromuscular junctions and cholinergic synapses.

Chemical Formula:

• C₁₂H₁₉N₂O₂⁺
• 

Mechanism of Action:

• Reversible AChE inhibitor.
• Also has some direct nicotinic agonist activity at NMJ.

Uses of Neostigmine:

• Myasthenia gravis
• Reversal of non-depolarizing neuromuscular blockers (e.g. tubocurarine)
• Postoperative ileus and urinary retention

Side Effects of Neostigmine:

• Bradycardia
• Salivation
• Muscle cramps
• Diarrhea
• Hypotension

SAR of Neostigmine:

1. Carbamate group:

   • Forms a reversible covalent bond with AChE → temporary inhibition.

2. Quaternary ammonium group:

   • Mimics choline portion of acetylcholine.
   • Prevents CNS penetration; acts peripherally.

3. Phenolic ring:

   • Enhances binding to acetylcholinesterase via interactions at peripheral sites.

4. Steric hindrance:

   • Affects rate of carbamoylation and decarbamoylation of the enzyme.

General Synthesis:

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