Anticholinesterase activity of compounds related to geneserine tautomers. N-Oxides and 1,2-oxazines.

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Yu QS, Zhu X, Holloway HW, Whittaker NF, Brossi A, Greig NH

Anticholinesterase activity of compounds related to geneserine tautomers. N-Oxides and 1,2-oxazines.

J Med Chem. 2002 Aug 15;45(17):3684-91.

PubMed ID
12166941 [ View in PubMed
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Abstract

A series of phenylcarbamate analogues of geneserine (8, 10, 12, 14) were synthesized from their counterparts, the phenylcarbamate analogues of physostigmine (2-5), by oxidation. The geneserine analogues can undergo tautomerism between N-oxide and 1,2-oxazine structures in a pH- and time-dependent manner. Assessment by (1)H NMR indicated that the N-oxide structure is adopted at neutral pH and that the compound exists in an equilibrium between several epimers. Evaluation of their biological action to inhibit human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), ex vivo, demonstrated that the N-oxide (7, 9, 11, 13, 15) and 1,2-oxazine (6, 8, 10, 12, 14) structures possessed similar potencies against AChE, but the latter structures were more potent against BChE. With the exception of the BChE selective inhibitor, 12, none of the geneserine analogues were as potent or enzyme subtype selective as their physostigmine analogue counterparts.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
DonepezilAcetylcholinesteraseIC 50 (nM)22837Details
GalantamineAcetylcholinesteraseIC 50 (nM)800837Details
Huperzine AAcetylcholinesteraseIC 50 (nM)47837Details
RivastigmineAcetylcholinesteraseIC 50 (nM)4150837Details
TacrineAcetylcholinesteraseIC 50 (nM)190837Details