What can you do to increase the selectivity of acetylcholine for nicotinic receptors?

• A. Add a methyl group to the alpha-carbon
• B. Remove a methyl group from the nitrogen
• C. Replace the nitrogen with sulfur
• D. Extend the ethylene bridge

Answer: (A)

Think about how acetylcholine sits in the nicotinic receptor binding pocket. The pocket favors a positively charged, compact head and engages the surrounding hydrophobic/aromatic regions to stabilize binding via cation-π interactions and hydrophobic contacts. Adding a methyl group to the alpha-carbon of the acetyl moiety increases steric bulk and hydrophobic character right near the head. This can improve how the molecule packs into the nicotinic binding site, enhancing the favorability of its interactions there more than at muscarinic sites, and thus boosting selectivity for nicotinic receptors. Other small changes either don’t improve the fit in the nicotinic pocket or disrupt essential features needed for binding altogether.