Characterization of the antiabsence effects of SCH 50911, a GABA-B receptor antagonist, in the lethargic mouse, gamma-hydroxybutyrate, and pentylenetetrazole models.
Recent studies have shown that gamma-aminobutyric acidB (GABAB) receptor antagonists suppress absence seizures in animal models. (+)-5,5-Dimethyl-2-morpholineacetic acid, hydrochloride (SCH 50911) is a new GABAB antagonist that is structurally dissimilar to previously studied GABAB antagonists such as 3-aminopropyl-diethoxymethyl-phosphinic acid (CGP 35348), 3-aminopropyl-n-butyl-phosphinic acid (CGP 36742) or 3-aminopropyl-cyclohexylmethyl-phosphinic acid (CGP 46381). In this study we measured the antiabsence effects of SCH 50911 in three animal models: the lethargic (lh/lh) mutant mouse, which has spontaneous absence seizures; and two rat models in which absence seizures were induced by administration of either gamma-hydroxybutyrate or pentylenetetrazole. SCH 50911 abolished seizures in all three models in a dose-dependent fashion (ID100 = 8-170 mumol/kg). In each model SCH 50911 was more potent (ID50 = 2-22 mumol/kg) than the following antiabsence compounds: the GABAB antagonist CGP 35348 (ID50 = 210-890 mumol/kg); ethosuximide (ID50 < or = 142-1240 mumol/kg); trimethadione (ID50 = 520-1100 mumol/kg); and valproic acid (ID50 = 900-2360 mumol/kg). SCH 50911 was equipotent with the GABAB antagonist CGP 46381 (ID50 = 20 mumol/kg) in the lh/lh mouse model. These findings suggest that antiabsence activity may be a defining feature of GABAB receptor antagonists and provide a rationale for pursuing clinical trials of GABAB receptor antagonists in human patients with absence seizures.
Hosford
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Department of Medicine (Neurology), Duke University, Duke University Medical Center, Durham, North Carolina, USA.
Wang
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Y
Liu
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Snead
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D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004569:Electroencephalography; D004832:Epilepsy, Absence / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D018756:GABA Antagonists / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use*; D010433:Pentylenetetrazole; D051381:Rats; D012978:Sodium Oxybate
C095804:(+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid; D000927:Anticonvulsants; D018756:GABA Antagonists; D009025:Morpholines; D012978:Sodium Oxybate; D010433:Pentylenetetrazole