Alzheimerâs
disease (AD) is the most common neurodegenerative
disorder worldwide. Ongoing research to develop AD treatments has
characterized multiple drug targets including the cholinergic system,
amyloid-ÎČ peptide, phosphorylated tau, and neuroinflammation.
These systems have the potential to interact to either drive or slow
AD progression. Promising agents that simultaneously impact many of
these drug targets are the AD experimental drug Posiphen and its enantiomer
phenserine that, currently, are separately being evaluated in clinical
trials. To define the cholinergic component of these agents, the anticholinesterase
activities of a ligand dataset comprising Posiphen and primary metabolites
((+)-N1-norPosiphen, (+)-N8-norPosiphen, and (+)-N1,N8-bisnorPosiphen)
were characterized and compared to those of the enantiomer phenserine.
The âtargetâ dataset involved the human cholinesterase
enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE).
Binding interactions between the ligands and targets were analyzed
using Autodock 4.2. The computationally determined inhibitory action
of these ligands was then compared to
ex vivo
laboratory-measured
values versus human AChE and BChE. While Posiphen lacked AChE inhibitory
action, its major and minor metabolites (+)-N1-norPosiphen and (+)-N1,N8-bisnorPosiphen,
respectively, possessed modest AChE inhibitory activity, and Posiphen
and all metabolites lacked BChE action. Phenserine, as a positive
control, demonstrated AChE-selective inhibitory action. In light of
AChE inhibitory action deriving from a major and minor Posiphen metabolite,
current Posiphen clinical trials in AD and related disorders should
additionally evaluate AChE inhibition; particularly if Posiphen should
be combined with a known anticholinesterase, since this drug class
is clinically approved and the standard of care for AD subjects, and
excessive AChE inhibition may impact drug tolerability.