Referenced in: none

Automatically associated channels: Kv1.1 , Kv1.2 , Kv1.3 , Kv1.4 , Kv1.5 , Kv1.6 , Kv3.1 , Kv4.2

Title: Novel nonpeptide agents potently block the C-type inactivated conformation of Kv1.3 and suppress T cell activation.

Authors: A Nguyen, J C Kath, D C Hanson, M S Biggers, P C Canniff, C B Donovan, R J Mather, M J Bruns, H Rauer, J Aiyar, A Lepple-Wienhues, G A Gutman, S Grissmer, M D Cahalan, K G Chandy

Journal, date & volume: Mol. Pharmacol., 1996 Dec , 50, 1672-9

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/8967992

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.