title: UK-78,282, a novel piperidine compound that potently blocks the Kv1.3 voltage-gated potassium channel and inhibits human T cell activation.
abstract: 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.
authors.affiliation: Pfizer Inc., Central Research Division, Groton, Connecticut 06340, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Hanson
authors.forename: A
authors.initials: A
authors.lastname: Nguyen
authors.forename: R J
authors.initials: RJ
authors.lastname: Mather
authors.forename: H
authors.initials: H
authors.lastname: Rauer
authors.forename: K
authors.initials: K
authors.lastname: Koch
authors.forename: L E
authors.initials: LE
authors.lastname: Burgess
authors.forename: J P
authors.initials: JP
authors.lastname: Rizzi
authors.forename: C B
authors.initials: CB
authors.lastname: Donovan
authors.forename: M J
authors.initials: MJ
authors.lastname: Bruns
authors.forename: P C
authors.initials: PC
authors.lastname: Canniff
authors.forename: A C
authors.initials: AC
authors.lastname: Cunningham
authors.forename: K A
authors.initials: KA
authors.lastname: Verdries
authors.forename: E
authors.initials: E
authors.lastname: Mena
authors.forename: J C
authors.initials: JC
authors.lastname: Kath
authors.forename: G A
authors.initials: GA
authors.lastname: Gutman
authors.forename: M D
authors.initials: MD
authors.lastname: Cahalan
authors.forename: S
authors.initials: S
authors.lastname: Grissmer
authors.forename: K G
authors.initials: KG
authors.lastname: Chandy
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D001667:Binding, Competitive; D019556:COS Cells; D002417:Cattle; D018999:Charybdotoxin / Q000378:metabolism / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007457:Iodine Radioisotopes; D015640:Ion Channel Gating / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew; D012414:Rubidium Radioisotopes; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D019789:Tetraethylammonium / Q000378:metabolism / Q000494:pharmacology
chemical_list: C120256:4-(diphenylmethoxymethyl)-1-(3-(4-methoxyphenyl)propyl)piperidine; D001559:Benzhydryl Compounds; D007166:Immunosuppressive Agents; D007457:Iodine Radioisotopes; D010880:Piperidines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D012414:Rubidium Radioisotopes; D018999:Charybdotoxin; D019789:Tetraethylammonium