title: Novel nonpeptide agents potently block the C-type inactivated conformation of Kv1.3 and suppress T cell activation.
abstract: The nonpeptide agent CP-339,818 (1-benzyl-4-pentylimino-1,4-dihydroquinoline) and two analogs (CP-393,223 and CP-394,322) that differ only with respect to the type of substituent at the N1 position, potently blocked the Kv1.3 channel in T lymphocytes. A fourth compound (CP-393,224), which has a smaller and less-lipophilic group at N1, was 100-200-fold less potent, suggesting that a large lipophilic group at this position is necessary for drug activity. CP-339,818 blocked Kv1.3 from the outside with a IC50 value of approximately 200 nM and 1:1 stoichiometry and competitively inhibited 125I-charybdotoxin from binding to the external vestibule of Kv1.3. This drug inhibited Kv1.3 in a use-dependent manner by preferentially blocking the C-type inactivated state of the channel. CP-339,818 was a significantly less potent blocker of Kv1.1, Kv1.2, Kv1.5, Kv1.6, Kv3.1-4, and Kv4.2; the only exception was Kv1.4, a cardiac and neuronal A-type K+ channel. CP-339,818 had no effect on two other T cell channels (I(CRAC) and intermediate-conductance K(Ca)) implicated in T cell mitogenesis. This drug suppresses human T cell activation, suggesting that blockade of Kv1.3 alone is sufficient to inhibit this process.
authors.affiliation: Department of Physiology and Biophysics, University of California, Irvine 92717, USA.
authors.forename: A
authors.initials: A
authors.lastname: Nguyen
authors.forename: J C
authors.initials: JC
authors.lastname: Kath
authors.forename: D C
authors.initials: DC
authors.lastname: Hanson
authors.forename: M S
authors.initials: MS
authors.lastname: Biggers
authors.forename: P C
authors.initials: PC
authors.lastname: Canniff
authors.forename: C B
authors.initials: CB
authors.lastname: Donovan
authors.forename: R J
authors.initials: RJ
authors.lastname: Mather
authors.forename: M J
authors.initials: MJ
authors.lastname: Bruns
authors.forename: H
authors.initials: H
authors.lastname: Rauer
authors.forename: J
authors.initials: J
authors.lastname: Aiyar
authors.forename: A
authors.initials: A
authors.lastname: Lepple-Wienhues
authors.forename: G A
authors.initials: GA
authors.lastname: Gutman
authors.forename: S
authors.initials: S
authors.lastname: Grissmer
authors.forename: M D
authors.initials: MD
authors.lastname: Cahalan
authors.forename: K G
authors.initials: KG
authors.lastname: Chandy
mesh_terms: D006367:HeLa Cells; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects*; D009154:Mutation; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000737:chemistry; D011487:Protein Conformation; D051672:Shal Potassium Channels; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
chemical_list: C497018:KCND2 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D051672:Shal Potassium Channels