Inhibition of acetylcholinesterase from electric eel by (−)‐ and (+)‐physostigmine and related compounds

Abstract Unnatural (+)-physostigmine (2) inhibited acetylcholinesterase (AChE) from electric eel considerably less than natural (−)-physostigmine ( 1 ), but 2 may because of its possible lower toxicity still be an interesting anticholinesterase agent. (−)-Eseroline ( 3 ), a major metabolite of (−)-physostigmine (1) and a potent narcotic analgetic, and its unnatural (+)-antipode ( 4 ), were both poor inhibitors of the enzyme. (−)-Dihydrose-cophysostigmine ( 5 ), a ring-open analog of (−)-physostigmine was less, but (−)- N -methylphysostigmine ( 6 ) much more potent than the natural alkaloid. The availability of compounds related to (−)- and (+)-physotigmine by improved chemical synthesis suggests that further structural variation may well lead to other biologically interesting AChE inhibitors. Physostigmine (Eserine) Eseroline Cholinesterase