Effects of a Cognition‐enhancer, Linopirdine (DuP 996), on M‐type Potassium Currents (IK(M)) Some Other Voltage‐ and Ligand‐gated Membrane Currents in Rat Sympathetic Neurons

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Abstract
Linopirdine is a cognition enhancer which augments depolarization‐induced transmitter release in the cortex and which is under consideration for potential treatment of Alzheimer's disease. It has previously been reported to inhibit M‐type K+ currents in rat hippocampal neurons. In the present experiments we have tested its effect on whole‐cell M‐currents and single M‐channels, and on a range of other membrane currents, in dissociated rat superior cervical sympathetic ganglion cells. Linopirdine inhibited the whole‐cell M‐current with an IC50 of 3.4 μM and blocked M‐channels recorded in excised outside‐out membrane patches but not in inside‐out patches. This suggests that linopirdine directly blocks M‐channels from the outside. It was much less effective in inhibiting other voltage‐gated potassium currents [delayed rectifier (IK(v)), IC50 63 μM; transient (IA) current, IC50 69 μM] and produced no detectable inhibition of the fast and slow Ca2+‐activated K+ currents Ic and IAHP or of a hyperpolarization‐activated cation current (IQ/Ih), at 10–30 μM. However, it reduced acetylcholine‐activated nicotinic currents and GABA‐activated Cl‐ currents with IC50 values of 7.6 and 26 μM respectively. It is concluded that linopirdine shows some 20–fold selectivity for M‐channels among different K+ channels but can also block some transmitter‐gated channels. The relationship between M‐channel block and the central actions of linopirdine are discussed.