title: GBR12909 possesses anticonvulsant activity in zebrafish and rodent models of generalized epilepsy but cardiac ion channel effects limit its clinical utility.
abstract: OBJECTIVE
  GBR12909 has been reported to possess anticonvulsant activity with focal brain perfusion to the hippocampus of pilocarpine, although an earlier publication suggested any anticonvulsant effects were only mild. Here we further explored the anticonvulsant potential of GBR12909 with a suite of anticonvulsant assays in both zebrafish and mammals and then explored whether it possessed any QT effects which might limit clinical utility.
  
  
  METHODS
  We assessed the anticonvulsant effects of GBR12909 in zebrafish pentylenetetrazole (PTZ), mammalian maximal electroshock and PTZ models of generalized epilepsy and a rodent hippocampal kindling model. Cardiac effects were assessed in zebrafish and man.
  
  
  RESULTS
  GBR12909 possesses anticonvulsant activity in zebrafish and rodent models of generalized epilepsy. However, phase 1 human data indicated potential QT effects. Subsequent testing in a zebrafish QT assay confirmed marked arrhythmogenic potential.
  
  
  CONCLUSIONS
  Further clinical development of GBR12909 in epilepsy was considered inappropriate because of insufficient window between the therapeutic effects and the cardiac arrhythmia problems identified in zebrafish assays. Any further development based on this mechanism of action should avoid the GBR12909 chemical scaffold, or involve structure-activity dissociation of its neurological and cardiac effects.
authors.affiliation: DanioLabs Ltd., Cambridge, UK. paul.goldsmith@daniolabs.com
authors.forename: Paul
authors.initials: P
authors.lastname: Goldsmith
authors.forename: Zoe
authors.initials: Z
authors.lastname: Golder
authors.forename: Julia
authors.initials: J
authors.lastname: Hunt
authors.forename: Stephane
authors.initials: S
authors.lastname: Berghmans
authors.forename: Derek
authors.initials: D
authors.lastname: Jones
authors.forename: James P
authors.initials: JP
authors.lastname: Stables
authors.forename: Lauren
authors.initials: L
authors.lastname: Murphree
authors.forename: Diane
authors.initials: D
authors.lastname: Howden
authors.forename: Paul E
authors.initials: PE
authors.lastname: Newton
authors.forename: Frances M
authors.initials: FM
authors.lastname: Richards
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D004285:Dogs; D018765:Dopamine Uptake Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D004562:Electrocardiography; D004827:Epilepsy / Q000188:drug therapy*; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D010879:Piperazines / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015027:Zebrafish
chemical_list: D000927:Anticonvulsants; D018765:Dopamine Uptake Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; D010879:Piperazines; C043425:vanoxerine