Potent and selective pharmacodynamic synergy between the metabotropic glutamate receptor subtype 2–positive allosteric modulator JNJ‐46356479 and levetiracetam in the mouse 6‐Hz (44‐mA) model

Abstract

These studies demonstrate a synergistic interaction of JNJ-46356479 with LEV, whereas no such effect occurred for JNJ-46356479 with either VPA or LTG. The synergy seems therefore to be specific to LEV, and the combination LEV/mGlu PAM has the potential to result in a rational polypharmacy approach to treat patients with refractory epilepsy, once it has been confirmed in clinical studies.

Progress report on new antiepileptic drugs: A summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). I. Drugs in preclinical and early clinical development

“…Studies of levetiracetam with selective mGlu2 PAM tool compounds in corneal kindled mice confirm a pharmacodynamic interaction in both percentage of animals protected and marked reductions in seizure severity scores. 26 In summary, JNJ-40411813 is potently effective in the 6-Hz mouse assay at both 32-and 44-mA pharmacoresistant stimulus intensities. Furthermore, whereas levetiracetam loses potency and efficacy in the 44-mA test, efficacy and potency are reestablished at much lower dosages when levetiracetam is coadministered with a subprotective dose of JNJ-40411813 or other mGlu2 PAMs.…”

“…In the mouse corneal kindling model, tool compound mGlu2 PAMs are active in protecting against seizure expression and in reducing seizure severity in a dose‐dependent and mechanistically specific manner. JNJ‐40411813 (1‐butyl‐3‐chloro‐4‐[4‐phenyl‐1‐piperidinyl]‐2[1H]‐pyridinone), a modestly potent mGlu2 PAM, was not active at 100 mg/kg sc in the corneal kindled mouse and was also inactive in the MES and sc PTZ models, with ED 50 estimates > 100 mg/kg when administered sc.…”

“…The data with other selective mGlu2 PAMs (preclinical tool compounds JNJ‐46356479 and JNJ‐42153605) and agonists (LY404039) suggested potency of the mGlu2 PAM or agonist as the most significant contributor of synergy . The synergy in the 6‐Hz 44‐mA model is observed exclusively with AEDs that bind SV2A and not with AEDs that have other mechanisms of action such as lamotrigine, valproic acid, carbamazepine, and diazepam (Janssen Research & Development, data on file). Studies of levetiracetam with selective mGlu2 PAM tool compounds in corneal kindled mice confirm a pharmacodynamic interaction in both percentage of animals protected and marked reductions in seizure severity scores …”

“…(1-butyl-3-chloro-4-[4-phenyl-1-piperidinyl]-2 [1H]-pyridinone), a modestly potent mGlu2 PAM, 25,26 was not active at 100 mg/kg sc in the corneal kindled mouse and was also inactive in the MES and sc PTZ models, with ED 50 estimates > 100 mg/kg when administered sc.…”

Targeting metabotropic glutamate receptors in the treatment of epilepsy: rationale and current status

“…Two elegant studies from the same research group [71,72] addressed the important issue of how group-II mGlu receptor ligands interact with classical anticonvulsant drugs using the 6-Hz model of psychomotor seizures in mice. In the first study [71] the Authors were able to demonstrate a pharmacological synergism between levetiracetam and three drugs that activate mGlu 2 receptors: the selective mGlu 2 receptor PAMs, JNJ-42153605 (3-(Cyclopropylmethyl)-7-(4-phenyl-1-piperidinyl)-8-(trifluoromethyl) [1,2,4]triazolo[4,3-a]pyridine) and JNJ-40411813 (1-butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-(1H)-pyridone), and the potent mGlu 2/3 receptor agonist, LY404039 ((1R,4S,5S,6S)-4-amino-2-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid 2,2-dioxide).…”