JZP-4 is a potent
calcium and
sodium channel blocker, which is currently being evaluated in patients as an
anticonvulsant and mood stabilizer. In the current studies,
JZP-4 was evaluated in a variety of animal models for
anticonvulsant, antimania and
antidepressant activity. In the mouse and rat maximal electroshock models,
JZP-4 was slightly more potent than LTG. In the mouse
pentylenetetrazole induced
seizures model,
JZP-4 was approximately twice as potent as
lamotrigine in prolonging the time to clonus. In the mouse 6-Hz model for
drug resistant or
refractory epilepsy,
JZP-4 had potent
anticonvulsant activity at all current intensities, whereas LTG was active at only the lowest current intensity. In the mouse
amphetamine-
chlordiazepoxide model for
antimanic effects,
JZP-4, but not LTG, produced dose-related and significant effects at 3 and 10 mg/kg i.p. In the rat forced swim model of
antidepressant activity,
JZP-4 (30 mg/kg i.p.) produced a significant reduction in immobility and an increase in climbing behavior. LTG (30 mg/kg i.p.) produced similar effects but these effects did not achieve statistical significance. The specificity of this
antidepressant response was confirmed in the rat locomotor test. In this test,
JZP-4 produced dose-related and significant reductions in locomotor activity, indicating that it was not a
CNS stimulant. LTG produced no significant effects in the rat locomotor test. The studies have demonstrated that
JZP-4 has greater potency and efficacy than LTG in models of
refractory epilepsy,
antidepressant activity and antimania activity. The variance between the effects of LTG and
JZP-4 may be related to the greater potency at
sodium channels or the additional pharmacological actions of
JZP-4 on
calcium channels.