In vivo pharmacological effects of JZP-4, a novel anticonvulsant, in models for anticonvulsant, antimania and antidepressant activity.

Abstract

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.

• Authors: Mark M Foreman, Taleen Hanania, Sharon C Stratton, Karen S Wilcox, H Steve White, James P Stables, Mark Eller
• Journal: Pharmacology, biochemistry, and behavior (Pharmacol Biochem Behav) Vol. 89 Issue 4 Pg. 523-34 (Jun 2008) ISSN: 0091-3057 [Print] United States
• PMID: 18377968 (Publication Type: Journal Article)

Chemical References

• Anticonvulsants
• Antidepressive Agents
• Antimanic Agents
• Calcium Channel Blockers
• Pyrazines
• Sodium Channel Blockers
• Triazines
• 3-(2,3,5-trichlorophenyl)pyrazine-2,6-diamine
• Lamotrigine

Topics

• Animals
• Anticonvulsants (chemistry, pharmacology)
• Antidepressive Agents (chemistry, pharmacology)
• Antimanic Agents (chemistry, pharmacology)
• Behavior, Animal (drug effects)
• Calcium Channel Blockers (chemistry, pharmacology)
• Central Nervous System (drug effects)
• Disease Models, Animal
• Epilepsy (drug therapy)
• Humans
• Kindling, Neurologic (drug effects)
• Lamotrigine
• Male
• Mice
• Molecular Structure
• Motor Activity (drug effects)
• Pyrazines (chemistry, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Seizures (chemically induced, drug therapy)
• Sodium Channel Blockers (chemistry, pharmacology)
• Triazines (pharmacology)