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

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Abstract
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 86Rb efflux assay. This compound blocks Kv1.3 with a IC50 of ∼200 nM and 1 : 1 stoichiometry. A closely related compound, CP‐190,325, containing a benzyl moiety in place of the benzhydryl in UK‐78,282, is significantly less potent. Three lines of evidence indicate that UK‐78,282 inhibits Kv1.3 in a use‐dependent manner by preferentially blocking and binding to the C‐type inactivated state of the channel. Increasing the fraction of inactivated channels by holding the membrane potential at −50 mV enhances the channel's sensitivity to UK‐78,282. Decreasing the number of inactivated channels by exposure to ∼160 mM external K+ decreases the sensitivity to UK‐78,282. Mutations that alter the rate of C‐type inactivation also change the channel's sensitivity to UK‐78,282 and there is a direct correlation between τh and IC50 values. Competition experiments suggest that UK‐78,282 binds to residues at the inner surface of the channel overlapping the site of action of verapamil. Internal tetraethylammonium and external charybdotoxin do not compete UK‐78,282's action on the channel. UK‐78,282 displays marked selectivity for Kv1.3 over several other closely related K+ channels, the only exception being the rapidly inactivating voltage‐gated K+ channel, Kv1.4. UK‐78,282 effectively suppresses human T‐lymphocyte activation. British Journal of Pharmacology (1999) 126, 1707–1716; doi:10.1038/sj.bjp.0702480