UK-78,282, a novel piperidine compound that potently blocks the Kv1.3 voltage-gated potassium channel and inhibits human T cell activation

1 UK-78,282, a novel piperidine blocker of the T lymphocyte voltage-gated K + channel, Kv1.3, was discovered by screening a large compound file using a high-throughput Rb-86 efflux assay. This compound blocks Kv1.3 with a IC50 of similar to 200 nM and 1:1 stoichiometry. A closely related compound, CP -190,325, containing a benzyl moiety in place of the benzhydryl in UK-78,28 2, is significantly less potent. 2 Three lines of evidence indicate that UK-78,282 inhibits Kv1.3 in a use-d ependent manner by preferentially blocking and binding to the C-type inacti vated state of the channel. Increasing the fraction of inactivated channels by holding the membrane potential at -50 mV enhances the channel's sensiti vity to UK-78,282. Decreasing the number of inactivated channels by exposur e to similar to 160 mM external K+ decreases the sensitivity to UK-78,282. Mutations that alter the rate of C-type inactivation also change the channe l's sensitivity to UK-78,282 and there is a direct correlation between tau( h) and IC50 values. 3 Competition experiments suggest that UK-78,282 binds to residues at the i nner surface of the channel overlapping the site of action of verapamil. In ternal tetraethylammonium and external charybdotoxin do not compete UK-78,2 82's action on the channel. 4 UK-78,282 displays marked selectivity for Kv1.3 over several other closel y related K+ channels, the only exception being the rapidly inactivating vo ltage-gated K+ channel, Kv1.4. 5 UK-78,282 effectively suppresses human T-lymphocyte activation.