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Vol. 286, Issue 2, 709-717, August 1998
DuPont Merck Research Laboratories, Central Nervous System Diseases
Research, Wilmington, Delaware
Linopirdine [DuP 996, 3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one], a putative
cognition enhancing drug, increases acetylcholine release in rat brain
tissue and improves performance in animal models of learning and
memory. The mechanism whereby linopirdine enhances acetylcholine
release has been proposed to involve inhibition of the M-type
K+ current (IM). Our study examines the
selectivity of linopirdine for IM by determining its
effects on other ionic currents present in rat hippocampal
CA1 neurons using patch clamp techniques. Linopirdine was
found to block voltage-gated, calcium-activated and leak K+
currents in a dose-dependent manner. Of the seven currents measured, linopirdine was most selective for IM with an
IC50 of 2.4 ± 0.4 µM, followed by IC
(measured as a medium afterhyperpolarization tail current,
ImAHP) with an IC50 of 16.3 ± 2.4 µM.
Both IM and IC were completely suppressed by
linopirdine. At a concentration of 100 µM, linopirdine weakly
inhibited the K+ leak current, IL, the
transient outward current, IA, the delayed rectifier,
IK, and the slow component of IAHP, by 28 ± 8, 37 ± 10, 36 ± 9 and 52 ± 10 percent,
respectively. The mixed Na+/K+ inward
rectifying current, IQ, was essentially unaffected by linopirdine (IC50 >300 µM). These results indicate that
linopirdine selectively blocks IM at concentrations 
3 µM, the approximate EC50 for acetylcholine release
enhancement. Inhibition of other voltage-gated and calcium-activated
K+ currents could also contribute to enhanced
neurotransmitter release by linopirdine at intermediate
(IC) and high (IL, IA,
IK, IsAHP) concentrations.
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