WIN-17317-3 - NOVEL NONPEPTIDE ANTAGONIST OF VOLTAGE-ACTIVATED K-LYMPHOCYTES( CHANNELS IN HUMAN T)

We report the in vitro biological characterization of WIN 17317-3 nzyl -7-chloro-4-n-propylimino-1,4-dihydroquinoline hydrochloride), a novel inhibitor of voltage-activated (n-type) K+ channels in human T lympho cytes. WIN 17317-3 inhibits I-125-charybdotoxin binding to n-type K+ c hannels with an IC50 value of 83 +/- 4 nM. WIN 17317-3 demonstrates co mpetitive inhibition of I-125-charybdotoxin binding by increasing its dissociation constant without changing the total number of channels bo und and by having no effect on its dissociation rate constant. W1N 173 17-3 inhibits whole-cell, n-type K+ currents with characteristics indi cative of open channel block and has an IC50 value of 335 nM. The comp ound is 150-fold selective for n-type K+ channels, compared with Ca2+- activated, charybdotoxin-sensitive K+ channels in smooth muscle. In pu rified CD4(+) T lymphocytes activated with either anti-CD3 plus phorbo l ester or anti-CD3 plus anti-CD28, WIN 17317-3 decreases interleukin- 2 production with EC(50) values of 0.8 mu M and 1 mu M, respectively. WIN 17317-3 is a novel, potent, and selective nonpeptide n-type K+ cha nnel antagonist that inhibits interleukin-2 production in human T lymp hocytes.