If you replace the nitrogen on acetylcholine with sulfur, what is the expected activity relative to acetylcholine?

If you replace the nitrogen on acetylcholine with sulfur, what is the expected activity relative to acetylcholine?

• A. No activity
• B. Active cholinergic agonist but less potent
• C. More potent than acetylcholine
• D. Pure muscarinic antagonist

Answer: (B)

The key idea is how the charged amine in acetylcholine dictates binding to cholinergic receptors. Replacing nitrogen with sulfur changes the cationic center from a quaternary ammonium to a sulfonium-type structure. While sulfur can still carry a positive charge, it does so less effectively for receptor binding, and the altered size and electronic properties reduce the strength of the ionic interactions that position the molecule in the receptor’s binding site. As a result, the molecule can still activate cholinergic receptors (it's an agonist) but binds less tightly, so its potency is decreased compared to acetylcholine.

The key idea is how the charged amine in acetylcholine dictates binding to cholinergic receptors. Replacing nitrogen with sulfur changes the cationic center from a quaternary ammonium to a sulfonium-type structure. While sulfur can still carry a positive charge, it does so less effectively for receptor binding, and the altered size and electronic properties reduce the strength of the ionic interactions that position the molecule in the receptor’s binding site. As a result, the molecule can still activate cholinergic receptors (it's an agonist) but binds less tightly, so its potency is decreased compared to acetylcholine.