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.