Abstract—Blocking specific K� channels has been proposed
as a promising strategy for the treatment of neurodegenera-
tive diseases. Using a computational virtual screening ap-
proach and electrophysiological testing, we found four Aco-
nitum alkaloids are potent blockers of the delayed rectifier K�
channel in rat hippocampal neurons. In the present study, we
first tested the action of the four alkaloids on the voltage-gated K +;, Na +; and Ca2 +; currents in rat hippocampal neurons,
and then identified that talatisamine is a specific blocker for the delayed rectifier K +; channel. External application of tala-tisamine reversibly inhibited the delayed rectifier K +; current
(IK) with an IC50 value of 146.0 5.8 M in a voltage-dependent
manner, but exhibited very slight blocking effect on the voltage-gated Na +; and Ca2 +; currents even at the high concentration of
1–3 mM. Moreover, talatisamine exerted a significant hyperpo-
larizing shift of the steady-state activation, but did not influence
the steady state inactivation of IK and its recovery from inacti-
vation, suggesting that talatisamine had no allosteric action on
IK channel and was a pure blocker binding to the external pore
entry of the channel. Our present study made the first discovery
of potent and specific IK channel blocker from Aconitum alka-loids. It has been argued that suppressing K +; efflux by blocking
IK channel may be favorable for Alzheimer’s disease therapy.
Talatisamine can therefore be considered as a leading com-
pound worthy of further investigations. © 2008 IBRO. Published