title: Efficient characterization of use-dependent ion channel blockers by real-time monitoring of channel state.
abstract: Ion channels are important therapeutic targets for the treatment of a variety of conditions. Among ion channel blocking agents, use-dependent inhibitors can be especially effective therapeutic agents. Use dependence allows the selective inhibition of hyperactive neurons or tachycardiac myocytes, while minimizing effects on cells with normal activity. For voltage-gated channels, the use-dependent compounds typically bind to and inhibit a particular kinetic state that is induced by specific voltage changes. Drug discovery programs that focus on this class of drugs need to rank the use dependence of the compounds. A meaningful comparison among different molecules requires voltage clamp-based assays with continuous voltage control and compensation for or elimination of electrode drift-related effects. A method was developed based on automated electrophysiology in which voltage and frequency dependence of voltage-gated ion channel blockers can be compared using a protocol in which voltage error is compensated for in real time.
authors.affiliation: AVIVA Biosciences Corporation, San Diego, CA 92121, USA.
authors.forename: Huimin
authors.initials: H
authors.lastname: Tao
authors.forename: António
authors.initials: A
authors.lastname: Guia
authors.forename: Betty
authors.initials: B
authors.lastname: Xie
authors.forename: David
authors.initials: D
authors.lastname: Santaana
authors.forename: Grace
authors.initials: G
authors.lastname: Manalo
authors.forename: Jia
authors.initials: J
authors.lastname: Xu
authors.forename: Andrea
authors.initials: A
authors.lastname: Ghetti
mesh_terms: D002220:Carbamazepine / Q000494:pharmacology; D002460:Cell Line; D004594:Electrophysiology / Q000379:methods; D006801:Humans; D007700:Kinetics; D000077213:Lamotrigine; D008012:Lidocaine / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D049990:Membrane Transport Modulators / Q000494:pharmacology*; D008991:Monitoring, Physiologic / Q000379:methods; D009124:Muscle Proteins / Q000187:drug effects / Q000502:physiology*; D062553:NAV1.4 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D015203:Reproducibility of Results; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*; D013748:Tetracaine / Q000494:pharmacology; D014162:Transfection; D014227:Triazines / Q000494:pharmacology
chemical_list: D049990:Membrane Transport Modulators; D009124:Muscle Proteins; D062553:NAV1.4 Voltage-Gated Sodium Channel; C106251:SCN4A protein, human; D015222:Sodium Channels; D014227:Triazines; D013748:Tetracaine; D002220:Carbamazepine; D008012:Lidocaine; D000077213:Lamotrigine