In vivo pharmacological effects of JZP-4, a novel anticonvulsant, in models for anticonvulsant, antimania and antidepressant activity.
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.
Foreman
Mark M
MM
Jazz Pharmaceuticals, Palo Alto, CA 94304, United States. mforeman@jazzpharma.com
Hanania
Taleen
T
Stratton
Sharon C
SC
Wilcox
Karen S
KS
White
H Steve
HS
Stables
James P
JP
Eller
Mark
M
D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology*; D018692:Antimanic Agents / Q000737:chemistry / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology; D002490:Central Nervous System / Q000187:drug effects; D004195:Disease Models, Animal; D004827:Epilepsy / Q000188:drug therapy; D006801:Humans; D007696:Kindling, Neurologic / Q000187:drug effects; D000077213:Lamotrigine; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D026941:Sodium Channel Blockers / Q000737:chemistry / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology
D000927:Anticonvulsants; D000928:Antidepressive Agents; D018692:Antimanic Agents; D002121:Calcium Channel Blockers; D011719:Pyrazines; D026941:Sodium Channel Blockers; D014227:Triazines; C530485:3-(2,3,5-trichlorophenyl)pyrazine-2,6-diamine; D000077213:Lamotrigine