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-dihydroqui noline) and two analogs (CP-393,223 and CP-394,322) that differ only w ith respect to the type of substituent at the N1 position, potently bl ocked the Kv1.3 channel in T lymphocytes. A fourth compound (CP-393,22 4), which has a smaller and less-lipophilic group at N1, was 100-200-f old less potent, suggesting that a large lipophilic group at this posi tion is necessary for drug activity. CP-339,818 blocked Kv1.3 from the outside with a IC50 value of similar to 200 nM and 1:1 stoichiometry and competitively inhibited I-125-charybdotoxin from binding to the ex ternal vestibule of Kv1.3. This drug inhibited Kv1.3 in a use-dependen t manner by preferentially blocking the C-type inactivated state of th e 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 i nhibit this process.