title: Assessment of seizure liability of Org 306039, a 5-HT2c agonist, using hippocampal brain slice and rodent EEG telemetry.
abstract: BACKGROUND
  Evaluation of the seizure potential for a CNS-targeted pharmaceutical compound before it is administered to humans is an important part of development. The current in vitro and in vivo studies were undertaken to characterize the seizure potential of the potent and selective 5-HT2c agonist Org 306039.
  
  
  METHODS
  Rat hippocampal slices (n=5) were prepared and Org 306039 was applied over a concentration range of 0-1000μM. Male Sprague-Dawley rats, implanted with telemetry EEG recording electrodes received either vehicle (n=4) or 100mg/kg Org 306039 (n=4) by oral gavage daily for 10days. EEG was recorded continuously for 22±1h post-dose each day. Post-dose behavior observations were conducted daily for 2h. Body temperature was measured at 1 and 2h post-dose. On Day 7, blood samples were drawn for pharmacokinetic analysis of Org 306039.
  
  
  RESULTS
  In hippocampal slice, Org 306039 elicited a concentration-dependent increase in population spike area and number recorded from CA1 area, indicating seizure-genic potential. In telemetered rats, Org 306039 was associated with a decrease in body weight, a decrease in body temperature and the appearance of seizure-related behaviors and pre-seizure waveforms on EEG. One rat exhibited an overt seizure. Plasma concentrations of Org 306039 were similar among the 4 rats in the Org-treated group. Small group size made it difficult to determine a PK-PD relationship.
  
  
  CONCLUSIONS
  These results indicate that the in vitro and in vivo models complement each other in the characterization of the seizure potential of CNS-targeted compounds such as the 5-HT2c agonist Org 306039.
authors.affiliation: Discovery Sciences Support, Merck Research Laboratories, 2015 Galloping Hill Road, Mailstop K15-2018B, Kenilworth, NJ 07033, USA. Electronic address: carrie.markgraf@merck.com.
authors.forename: Carrie G
authors.initials: CG
authors.lastname: Markgraf
authors.affiliation: Psychiatry, Children's Hospital of Philadelphia UPenn School of Medicine ARC 515, 3615 Civic Center Blvd, Philadelphia, PA 19104-5127, USA. Electronic address: deboere@email.chop.edu.
authors.forename: Erik
authors.initials: E
authors.lastname: DeBoer
authors.affiliation: Safety Assessment, Merck Research Laboratories, 770 Sumneytown Pike, Lansdale, PA 19486, USA. Electronic address: jin.zhai@merck.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhai
authors.affiliation: Safety Assessment, Merck Research Laboratories, 770 Sumneytown Pike, Lansdale, PA 19486, USA. Electronic address: lara.cornelius@merck.com.
authors.forename: Lara
authors.initials: L
authors.lastname: Cornelius
authors.affiliation: Safety Assessment, Merck Research Laboratories, 770 Sumneytown Pike, Lansdale, PA 19486, USA.
authors.forename: Ying Ying
authors.initials: YY
authors.lastname: Zhou
authors.affiliation: Biotrial International, 3-7 Temple Avenue, London EC4Y 0HP, UK. Electronic address: cliona.macsweeney@biotrial.co.uk.
authors.forename: Cliona
authors.initials: C
authors.lastname: MacSweeney
mesh_terms: D000818:Animals; D004569:Electroencephalography; D006624:Hippocampus / Q000187:drug effects*; D008297:Male; D011083:Polycyclic Compounds / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced* / Q000503:physiopathology*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000008:administration & dosage / Q000633:toxicity*; D013686:Telemetry
chemical_list: C000601287:Org 306039; D011083:Polycyclic Compounds; D058826:Serotonin 5-HT2 Receptor Agonists
keywords: Behavior; Brain; CNS; Convulsion; Method; Obesity; Rat; Seizure; Serotonin; Temperature