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Abstract
<p class="first" id="d1612313e137">Donepezil is a potent, selective inhibitor of acetylcholinesterase,
which is used
for the treatment of Alzheimer's disease. Whole-cell patch-clamp technique and Western
blot analyses were used to study the effects of donepezil on the human ether-a-go-go-related
gene (hERG) channel. Donepezil inhibited the tail current of the hERG in a concentration-dependent
manner with an IC50 of 1.3 μM. The metabolites of donepezil, 6-ODD and 5-ODD, inhibited
the hERG currents in a similar concentration-dependent manner; the IC50 values were
1.0 and 1.5 μM, respectively. A fast drug perfusion system demonstrated that donepezil
interacted with both the open and inactivated states of the hERG. A fast application
of donepezil during the tail currents inhibited the open state of the hERG in a concentration-dependent
manner with an IC50 of 2.7 μM. Kinetic analysis of donepezil in an open state of the
hERG yielded blocking and unblocking rate constants of 0.54 µM(-1)s(-1) and 1.82 s(-1),
respectively. The block of the hERG by donepezil was voltage-dependent with a steep
increase across the voltage range of channel activation. Donepezil caused a reduction
in the hERG channel protein trafficking to the plasma membrane at low concentration,
but decreased the channel protein expression at higher concentrations. These results
suggest that donepezil inhibited the hERG at a supratherapeutic concentration, and
that it did so by preferentially binding to the activated (open and/or inactivated)
states of the channels and by inhibiting the trafficking and expression of the hERG
channel protein in the plasma membrane.
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