title: T-type calcium channel blockers that attenuate thalamic burst firing and suppress absence seizures.
abstract: Absence seizures are a common seizure type in children with genetic generalized epilepsy and are characterized by a temporary loss of awareness, arrest of physical activity, and accompanying spike-and-wave discharges on an electroencephalogram. They arise from abnormal, hypersynchronous neuronal firing in brain thalamocortical circuits. Currently available therapeutic agents are only partially effective and act on multiple molecular targets, including γ-aminobutyric acid (GABA) transaminase, sodium channels, and calcium (Ca(2+)) channels. We sought to develop high-affinity T-type specific Ca(2+) channel antagonists and to assess their efficacy against absence seizures in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model. Using a rational drug design strategy that used knowledge from a previous N-type Ca(2+) channel pharmacophore and a high-throughput fluorometric Ca(2+) influx assay, we identified the T-type Ca(2+) channel blockers Z941 and Z944 as candidate agents and showed in thalamic slices that they attenuated burst firing of thalamic reticular nucleus neurons in GAERS. Upon administration to GAERS animals, Z941 and Z944 potently suppressed absence seizures by 85 to 90% via a mechanism distinct from the effects of ethosuximide and valproate, two first-line clinical drugs for absence seizures. The ability of the T-type Ca(2+) channel antagonists to inhibit absence seizures and to reduce the duration and cycle frequency of spike-and-wave discharges suggests that these agents have a unique mechanism of action on pathological thalamocortical oscillatory activity distinct from current drugs used in clinical practice.
authors.affiliation: Zalicus Pharmaceuticals Ltd., Suite 301, 2389 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tringham
authors.forename: Kim L
authors.initials: KL
authors.lastname: Powell
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Cain
authors.forename: Kristy
authors.initials: K
authors.lastname: Kuplast
authors.forename: Janette
authors.initials: J
authors.lastname: Mezeyova
authors.forename: Manjula
authors.initials: M
authors.lastname: Weerapura
authors.forename: Cyrus
authors.initials: C
authors.lastname: Eduljee
authors.forename: Xinpo
authors.initials: X
authors.lastname: Jiang
authors.forename: Paula
authors.initials: P
authors.lastname: Smith
authors.forename: Jerrie-Lynn
authors.initials: JL
authors.lastname: Morrison
authors.forename: Nigel C
authors.initials: NC
authors.lastname: Jones
authors.forename: Emma
authors.initials: E
authors.lastname: Braine
authors.forename: Gil
authors.initials: G
authors.lastname: Rind
authors.forename: Molly
authors.initials: M
authors.lastname: Fee-Maki
authors.forename: David
authors.initials: D
authors.lastname: Parker
authors.forename: Hassan
authors.initials: H
authors.lastname: Pajouhesh
authors.forename: Manjeet
authors.initials: M
authors.lastname: Parmar
authors.forename: Terence J
authors.initials: TJ
authors.lastname: O'Brien
authors.forename: Terrance P
authors.initials: TP
authors.lastname: Snutch
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000187:drug effects*; D004832:Epilepsy, Absence / Q000517:prevention & control*; D006801:Humans; D010880:Piperidines; D013788:Thalamus / Q000187:drug effects* / Q000502:physiology
chemical_list: D000081:Acetamides; D001549:Benzamides; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D010880:Piperidines; C000629485:Z944