RT Journal Article
SR Electronic
T1 Novel nonpeptide agents potently block the C-type inactivated conformation of Kv1.3 and suppress T cell activation.
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1672
OP 1679
VO 50
IS 6
A1 A Nguyen
A1 J C Kath
A1 D C Hanson
A1 M S Biggers
A1 P C Canniff
A1 C B Donovan
A1 R J Mather
A1 M J Bruns
A1 H Rauer
A1 J Aiyar
A1 A Lepple-Wienhues
A1 G A Gutman
A1 S Grissmer
A1 M D Cahalan
A1 K G Chandy
YR 1996
UL http://molpharm.aspetjournals.org/content/50/6/1672.abstract
AB 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.