WIN 17317-3: novel nonpeptide antagonist of voltage-activated K+ channels in human T lymphocytes.

R J Hill, A M Grant, W Volberg, L Rapp, C Faltynek, D Miller, K Pagani, E Baizman, S Wang, J W Guiles

Department of Biochemistry, Sanofi Winthrop, Inc., Collegeville, Pennsylvania 19426, USA.

Molecular pharmacology 1995 Jul

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We report the in vitro biological characterization of WIN 17317-3 (1-benzyl-7-chloro-4-n-propylimino-1,4-dihydroquinoline hydrochloride), a novel inhibitor of voltage-activated (n-type) K+ channels in human T lymphocytes. WIN 17317-3 inhibits 125I-charybdotoxin binding to n-type K+ channels with an IC50 value of 83 +/- 4 nM. WIN 17317-3 demonstrates competitive inhibition of 125I-charybdotoxin binding by increasing its dissociation constant without changing the total number of channels bound and by having no effect on its dissociation rate constant. WIN 17317-3 inhibits whole-cell, n-type K+ currents with characteristics indicative of open channel block and has an IC50 value of 335 nM. The compound is 150-fold selective for n-type K+ channels, compared with Ca(2+)-activated, charybdotoxin-sensitive K+ channels in smooth muscle. In purified CD4+ T lymphocytes activated with either anti-CD3 plus phorbol ester or anti-CD3 plus anti-CD28, WIN 17317-3 decreases interleukin-2 production with EC50 values of 0.8 microM and 1 microM, respectively. WIN 17317-3 is a novel, potent, and selective nonpeptide n-type K+ channel antagonist that inhibits interleukin-2 production in human T lymphocytes.

Citation

R J Hill, A M Grant, W Volberg, L Rapp, C Faltynek, D Miller, K Pagani, E Baizman, S Wang, J W Guiles. WIN 17317-3: novel nonpeptide antagonist of voltage-activated K+ channels in human T lymphocytes. Molecular pharmacology. 1995 Jul;48(1):98-104