Acute behavioral and EEG effects of NW-1015 on electrically-induced afterdischarge in conscious monkeys

NV-1015 is a novel Na+ and Ca2+ channel blocker with broad spectrum anticon vulsant activity and an excellent safety margin. As the compound also shows sigma-1 receptor ligand properties it was deemed important to determine wh ether it possesses anticonvulsant properties in primates without causing be havioral and EEG abnormalities. Thus, the effects of NW-1015 on limbic elec trically-induced afterdischarge (AD) were evaluated in four cynomolgus monk eys, and its activity compared to a single effective dose of phenytoin (PHT ). The four;male cynomolgus monkeys were chronically implanted for EEG reco rdings, from cortex and limbic structures. AD was induced in limbic areas b y electrical stimulation. The effects of NW-1015 on the duration and the be havioral component of the AD were randomly tested at doses from 25 to 75 mg /kg and compared with the effects of PHT 50 mg/kg. Similarly to PHT, 50 mg/ kg of NW-1015 significantly shortened the EEG AD and almost abolished AD el icited behavioral seizure. Only the behavioral effects of AD were reduced a fter administration of 25 mg/kg p.o. NW-1015 did not cause EEG or intericta l behavioral alterations at doses up to 75 mg/kg p.o. These data further co nfirm the broad-spectrum anticonvulsant activity and a good safety profile of NW-1015 even in a primate model of complex partial seizures and suggest that its affinity for sigma-1 receptors is behaviorally irrelevant. (C) 200 0 Elsevier Science B.V. All rights reserved.