A 62-year-old man with Alzheimer's disease is started on donepezil. The drug inhibits acetylcholinesterase predominantly at which molecular site to prolong ACh action?
- A Anionic site of AChE, preventing ACh binding by charge repulsion
- B Esteratic (serine) site of AChE, forming a reversible carbamylated enzyme intermediate
- C Peripheral anionic site of AChE via hydrophobic interaction, slowing ACh approach to the catalytic triad ✓
- D Acylation site of AChE, forming an irreversible phosphorylated enzyme complex
Correct answer: C. Peripheral anionic site of AChE via hydrophobic interaction, slowing ACh approach to the catalytic triad
Explanation
Donepezil (a piperidine-based AChEI) binds the peripheral anionic site (PAS) of AChE through pi-stacking and hydrophobic interactions, blocking entry of ACh into the active-site gorge — a dual-site inhibition that is distinct from the classical esteratic-site carbamylation seen with physostigmine/neostigmine. This mechanism underlies its longer duration and once-daily dosing. Option B describes physostigmine/rivastigmine; option D describes irreversible OP compounds.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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