title: Novel inhibitors of potassium ion channels on human T lymphocytes.
abstract: The in vitro biological characterization of a series of 4-(alkylamino)-1,4-dihydroquinolines is reported. These compounds are novel inhibitors of voltage-activated n-type potassium ion (K+) channels in human T lymphocytes. This series, identified from random screening, was found to inhibit [125I]charybdotoxin binding to n-type K+ channels with IC50 values ranging from 10(-6) to 10(-8) M. These analogs also inhibit whole cell n-type K+ currents with IC50 values from 10(-5) to 10(-7) M. The preparation of a series of new 4-(alkylamino)-1,4-dihydroquinolines is described. Structure-activity relationships are discussed. Naphthyl analog 7c, the best compound prepared, exhibited > 100-fold selectivity for inhibition of [125I]charybdotoxin binding to n-type K+ channels compared with inhibition of [3H]dofetilide binding to cardiac K+ channels. These compounds represent a potent and selective series of n-type K+ channel inhibitors that have the potential for further development as anti-inflammatory agents.
authors.affiliation: Sanofi Winthrop Inc., Collegeville, Pennsylvania 19426, USA.
authors.forename: W F
authors.initials: WF
authors.lastname: Michne
authors.forename: J W
authors.initials: JW
authors.lastname: Guiles
authors.forename: A M
authors.initials: AM
authors.lastname: Treasurywala
authors.forename: L A
authors.initials: LA
authors.lastname: Castonguay
authors.forename: C A
authors.initials: CA
authors.lastname: Weigelt
authors.forename: B
authors.initials: B
authors.lastname: Oconnor
authors.forename: W A
authors.initials: WA
authors.lastname: Volberg
authors.forename: A M
authors.initials: AM
authors.lastname: Grant
authors.forename: C C
authors.initials: CC
authors.lastname: Chadwick
authors.forename: D S
authors.initials: DS
authors.lastname: Krafte
mesh_terms: D018999:Charybdotoxin; D003198:Computer Simulation; D006801:Humans; D007457:Iodine Radioisotopes; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D008958:Models, Molecular; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D012604:Scorpion Venoms / Q000378:metabolism; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000737:chemistry* / Q000187:drug effects*
chemical_list: D007457:Iodine Radioisotopes; D015221:Potassium Channels; D011804:Quinolines; D012604:Scorpion Venoms; D018999:Charybdotoxin