Novel nonpeptide agents potently block the C-type inactivated conformation of Kv1.3 and suppress T cell activation.
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.
Nguyen
A
A
Department of Physiology and Biophysics, University of California, Irvine 92717, USA.
Kath
J C
JC
Hanson
D C
DC
Biggers
M S
MS
Canniff
P C
PC
Donovan
C B
CB
Mather
R J
RJ
Bruns
M J
MJ
Rauer
H
H
Aiyar
J
J
Lepple-Wienhues
A
A
Gutman
G A
GA
Grissmer
S
S
Cahalan
M D
MD
Chandy
K G
KG
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
C497018:KCND2 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D051672:Shal Potassium Channels