title: WIN 17317-3: novel nonpeptide antagonist of voltage-activated K+ channels in human T lymphocytes.
abstract: 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.
authors.affiliation: Department of Biochemistry, Sanofi Winthrop, Inc., Collegeville, Pennsylvania 19426, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Hill
authors.forename: A M
authors.initials: AM
authors.lastname: Grant
authors.forename: W
authors.initials: W
authors.lastname: Volberg
authors.forename: L
authors.initials: L
authors.lastname: Rapp
authors.forename: C
authors.initials: C
authors.lastname: Faltynek
authors.forename: D
authors.initials: D
authors.lastname: Miller
authors.forename: K
authors.initials: K
authors.lastname: Pagani
authors.forename: E
authors.initials: E
authors.lastname: Baizman
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.forename: J W
authors.initials: JW
authors.lastname: Guiles
mesh_terms: D002460:Cell Line; D018999:Charybdotoxin; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007457:Iodine Radioisotopes; D015640:Ion Channel Gating; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D012604:Scorpion Venoms / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism
chemical_list: D007376:Interleukin-2; D007457:Iodine Radioisotopes; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011804:Quinolines; D012604:Scorpion Venoms; C094805:WIN 17317-3; D018999:Charybdotoxin