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

Br J Pharmacol. 1999 Apr;126(8):1707-16. doi: 10.1038/sj.bjp.0702480.


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 86Rb efflux assay. This compound blocks Kv1.3 with a IC50 of approximately 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. 2 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 approximately 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 tau(h) and IC50 values. 3. 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. 4. 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. 5. UK-78,282 effectively suppresses human T-lymphocyte activation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Benzhydryl Compounds / pharmacology*
  • Binding, Competitive
  • COS Cells
  • Cattle
  • Charybdotoxin / metabolism
  • Charybdotoxin / pharmacology
  • HeLa Cells
  • Humans
  • Immunosuppressive Agents / pharmacology*
  • Iodine Radioisotopes
  • Ion Channel Gating / physiology
  • Lymphocyte Activation / drug effects*
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Piperidines / pharmacology*
  • Potassium Channel Blockers*
  • Potassium Channels / metabolism
  • Potassium Channels / physiology
  • Rats
  • Rats, Inbred Lew
  • Rubidium Radioisotopes
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / immunology
  • Tetraethylammonium / metabolism
  • Tetraethylammonium / pharmacology


  • 4-(diphenylmethoxymethyl)-1-(3-(4-methoxyphenyl)propyl)piperidine
  • Benzhydryl Compounds
  • Immunosuppressive Agents
  • Iodine Radioisotopes
  • Piperidines
  • Potassium Channel Blockers
  • Potassium Channels
  • Rubidium Radioisotopes
  • Charybdotoxin
  • Tetraethylammonium