title: A novel benzodiazepine that activates cardiac slow delayed rectifier K+ currents.
abstract: The slowly activating delayed rectifier K+ current, IKs, is an important modulator of cardiac action potential repolarization. Here, we describe a novel benzodiazepine, [L-364,373 [(3-R)-1, 3-dihydro-5-(2-fluorophenyl)-3-(1H-indol-3-ylmethyl)-1-methyl-2H- 1,4-benzodiazepin-2-one] (R-L3), that activates IKs and shortens action potentials in guinea pig cardiac myocytes. These effects were additive to isoproterenol, indicating that channel activation by R-L3 was independent of beta-adrenergic receptor stimulation. The increase of IKs by R-L3 was stereospecific; the S-enantiomer, S-L3, blocked IKs at all concentrations examined. The increase in IKs by R-L3 was greatest at voltages near the threshold for normal channel activation, caused by a shift in the voltage dependence of IKs activation. R-L3 slowed the rate of IKs deactivation and shifted the half-point of the isochronal (7.5 sec) activation curve for IKs by -16 mV at 0.1 microM and -24 mV at 1 microM. R-L3 had similar effects on cloned KvLQT1 channels expressed in Xenopus laevis oocytes but did not affect channels formed by coassembly of KvLQT1 and hminK subunits. These findings indicate that the association of minK with KvLQT1 interferes with the binding of R-L3 or prevents its action once bound to KvLQT1 subunits.
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. joseph_salata@merck.com
authors.forename: J J
authors.initials: JJ
authors.lastname: Salata
authors.forename: N K
authors.initials: NK
authors.lastname: Jurkiewicz
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: B E
authors.initials: BE
authors.lastname: Evans
authors.forename: H T
authors.initials: HT
authors.lastname: Orme
authors.forename: M C
authors.initials: MC
authors.lastname: Sanguinetti
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D051668:Delayed Rectifier Potassium Channels; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006352:Heart Ventricles / Q000187:drug effects; D006801:Humans; D007473:Ion Channels / Q000187:drug effects; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D016276:Ventricular Function; D014982:Xenopus laevis / Q000235:genetics
chemical_list: D051668:Delayed Rectifier Potassium Channels; D007473:Ion Channels; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; C113498:L 364373; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011943:Receptors, Adrenergic, beta; D001569:Benzodiazepines