Xf. Pei et al., Syntheses and biological evaluation of ring-C opened analogues of the cholinesterase inhibitors physostigmine, phenserine and cymserine, MED CHEM RE, 9(1), 1999, pp. 50-60
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.