Syntheses and biological evaluation of ring-C opened analogues of the cholinesterase inhibitors physostigmine, phenserine and cymserine

The ring-C of natural, 3aS, (-)-physostigmine (1), (-)-phenserine (2) and ( -)-cymserine (3) were cleaved by catalytic hydrogenation under acidic condi tion to give ring-C opened compounds (4-6). The tertiary amines (10-12) wer e prepared from methiodides (7-9) by reduction with NaBH4. Additionally, th e unnatural, 3aR, enantiomer of ring-C opened phenserine (14) was synthesiz ed from (+)-phenserine (13). All then were evaluated for anticholinesterase activity against human acetyl- and butyrylcholinesterase. Compounds 4-12 w ere found to have potent inhibitory activity and, with the exception of the methiodides (7-9), to retain the subtype selectivity provided them by thei r carbamate group. Interestingly, methiodide 8 possessed characteristics of potential value for treatment of mysathenia gravis. In contrast, compound 14 proved to be some 2 log-fold less active than its enantiomeric form (5). These studies conclusively demonstrate that the tricyclic structure of (-) -physostigmine (1) and analogs is not essential for their anticholinesteras e action, and that such activity for ring C opened compounds, similar to (- ) physostigmine and phenylcarbamates (1-3), is limited to their 3aS enantio mer.