Efficacy of mGlu2-positive allosteric modulators alone and in combination with levetiracetam in the mouse 6 Hz model of psychomotor seizures.
The metabotropic glutamate receptor subtype 2 (mGlu2) possesses both orthosteric and allosteric modulatory sites, are expressed in the frontal cortex and limbic structures, and can affect excitatory synaptic transmission. Therefore, mGlu2is a potential therapeutic target in the treatment of epilepsy. The present study seeks to evaluate the anticonvulsant potential of mGlu2-acting compounds.



The anticonvulsant efficacy of two selective mGlu2-positive allosteric modulators (PAMs) (JNJ-42153605 and JNJ-40411813/ADX71149) and one mGlu2/3receptor agonist (LY404039) were evaluated alone and in combination with the antiseizure drug levetiracetam (LEV) in the mouse 6 Hz model.



In the 6 Hz (32 mA stimulus intensity) model, median effective dose (ED50) values were determined for JNJ-42153605 (3.8 mg/kg), JNJ-40411813 (12.2 mg/kg), and LY404039 (10.9 mg/kg). At the 44 mA stimulus intensity, ED50values were determined for JNJ-42153605 (5.9 mg/kg), JNJ-40411813 (21.0 mg/kg), LY404039 (14.1 mg/kg), and LEV (345 mg/kg). In addition, subprotective doses of each mGlu2-acting compound, administered in combination with various doses of LEV, were able to shift the 6 Hz 44 mA ED50for LEV by >25-fold. When JNJ-42153605 was administered at varying doses in combination with a single dose of LEV (10 mg/kg), the potency of JNJ-42153605 was increased 3.7-fold. Similarly, when a moderately effective dose of LEV (350 mg/kg) was administered in combination with varying doses of JNJ-40411813, the potency of JNJ-40411813 was increased approximately 14-fold. Plasma levels of JNJ-40411813 and LEV were not different when administered alone or in combination, suggesting that increases in potency are not due to pharmacokinetic effects.



These studies suggest a potential positive pharmacodynamic effect of mGlu2-acting compounds in combination with LEV. If this effect is translated in a clinical setting, it can support a rational polypharmacy concept in treatment of epilepsy patients.
NeuroAdjuvants, Inc., Salt Lake City, Utah, U.S.A.|Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah, U.S.A.
Cameron S
CS
Metcalf
NeuroAdjuvants, Inc., Salt Lake City, Utah, U.S.A.|Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah, U.S.A.
Brian D
BD
Klein
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah, U.S.A.
Misty D
MD
Smith
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah, U.S.A.
Tim
T
Pruess
Janssen Research and Development, Beerse, Belgium.
Marc
M
Ceusters
Janssen Research and Development, Beerse, Belgium.
Hilde
H
Lavreysen
Janssen Cilag Belgium, Beerse, Belgium.
Stefan
S
Pype
Janssen Research and Development, Beerse, Belgium.|UCB Belgium, Anderlecht, Belgium, Belgium.
Nancy
N
Van Osselaer
Janssen Research and Development, Titusville, New Jersey, U.S.A.
Roy
R
Twyman
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah, U.S.A.|Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, Washington, U.S.A.
H Steve
HS
White
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001703:Biophysics; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use; D003499:Cyclic S-Oxides / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004597:Electroshock / Q000009:adverse effects; D017029:Epilepsy, Complex Partial / Q000188:drug therapy* / Q000209:etiology; D018683:Excitatory Amino Acid Agents / Q000627:therapeutic use*; D000077287:Levetiracetam; D008297:Male; D051379:Mice; D010889:Piracetam / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D045442:Rotarod Performance Test; D013239:Stereotyped Behavior / Q000502:physiology; D014227:Triazines / Q000627:therapeutic use
C577930:3-cyclopropylmethyl-7-(4-phenylpiperidin-1-yl)-8-trifluoromethyl(1,2,4)triazolo(4,3-a)pyridine; C517803:4-aminho-2-thiabicyclo(3.1.0)hexane-4,6-dicarboxylic acid; D000927:Anticonvulsants; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003499:Cyclic S-Oxides; D018683:Excitatory Amino Acid Agents; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; D014227:Triazines; C108822:metabotropic glutamate receptor 2; D000077287:Levetiracetam; D010889:Piracetam
Animal models; Combination studies; Levetiracetam; Metabotropic glutamate receptors; Psychomotor seizures