Clotrimazole analogues: effective blockers of the slow afterhyperpolarization in cultured rat hippocampal pyramidal neurones

1 The pharmacology of the slow afterhyperpolarization (sAHP) was studied in cultured rat hippocampal pyramidal neurones. 2 Clotrimazole its in vivo metabolite, 2-chlorophenyl-bisphenly-methanol (C BM) and the novel analogues, UCL 1880 and UCL 2027, inhibited the sI(AHP) W ith Similar IC(50)s (1-2 muM). 3 Clotrimazole and CBM also inhibited the high voltage-activated (HVA) Ca2 current in pyramidal neurones with IC(50)s of 4.7 muM and 2.2 muM respecti vely. UCL 1880 was a less effective Ca2+ channel blocker, reducing the HVA Ca2+ current by 50% at 10 muM. At concentrations up to 10 muM, UCL 2027 had no effect on the Ca2+ current, indicating that its effects on the sI(AHP) were independent of Ca2+ channel block. 4 Clotrimazole also inhibited both the outward holding current (IC50 = 2.8 muM) present at a potential of -50 mV and the apamin-sensitive medium AHP ( mAHP; IC50 approximate to 10 muM). The other clotrimazole analogues tested had smaller effects on these two currents. The present work also shows that 100 nM UCL 1848, an inhibitor of apamin-sensitive conductances, abolishes the mAHP. 5 Currents were recorded from HEK293 cells transfected with hSK1 and rSK2. The SK currents were very sensitive to inhibition by UCL 1848 but were not significantly reduced by the sI(AHP) inhibitor, UCL 2027 (10 muM). 10 muM U CL 1880 reduced the hSK1 current by 40%. 6 UCL 2027 appears to be the first relatively selective blocker of the sAHP to be described. Furthermore, the ability of UCL 2027 to block the sAHP with minimal effect on SK1 channel a ctivity questions the role of this channel in the sAHP.