To increase muscarinic receptor selectivity of acetylcholine, which modification is suggested?

• A. Add a methyl group to the beta-carbon
• B. Add a methyl group to the alpha-carbon
• C. Add a hydroxyl group to the beta-carbon
• D. Remove the beta-methyl group

Answer: (A)

Tuning how bulky the molecule is at the beta position of acetylcholine changes which receptor it prefers. Adding a methyl group to the beta-carbon increases steric bulk in a way that muscarinic receptors can accommodate, while nicotinic receptors are more sensitive to that extra bulk and bind less effectively. The essential features that let acetylcholine interact with receptors—the quaternary ammonium charge and the ester linkage—stay the same, so the molecule still engages receptors, but the beta-methyl makes it a better fit for muscarinic sites and worse for nicotinic ones. Other changes, like putting a hydroxyl on the beta-carbon or removing the beta-methyl, wouldn’t promote that muscarinic preference as effectively.