GalR2-positive allosteric modulator exhibits anticonvulsant effects in animal models.

Abstract

Galanin receptors type 1 (GalR1) and/or type 2 (GalR2) represent unique pharmacological targets for treatment of seizures and epilepsy. Previous studies have shown that the endogenous peptide ligand galanin exerts powerful anticonvulsant effect through activation of these two G protein-coupled receptors, which are highly expressed in the temporal lobe of rodent brain. Here we report the characterization of a putative GalR2-positive allosteric modulator CYM2503. CYM2503 potentiated the galanin-stimulated IP1 accumulation in HEK293 cells stably expressing GalR2 receptor, whereas it exhibited no detectable affinity for the (125)I galanin-binding site of GalR2 receptor, an effect consistent with that of a positive allosteric modulator. In the rat Li-pilocarpine status epilepticus model, CYM2503, injected intraperitoneally, increased the latency to first electrographic seizure and the latency to first stage 3 behavioral seizure, decreased the latency to the establishment of status epilepticus, and dramatically decreased the mortality. In a Li-pilocarpine seizure model in mice, CYM2503 increased the latency to first electrographic seizure and decreased the total time in seizure. CYM2503 also attenuated electroshock-induced seizures in mice. Thus, CYM2503 provides a starting point for the development of anticonvulsant therapy using the galanin R2 receptor as target.

• Authors: Xiaoying Lu, Edward Roberts, Fengcheng Xia, Manuel Sanchez-Alavez, Tianyu Liu, Roger Baldwin, Stephanie Wu, James Chang, Claude G Wasterlain, Tamas Bartfai
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 107 Issue 34 Pg. 15229-34 (Aug 24 2010) ISSN: 1091-6490 [Electronic] United States
• PMID: 20660766 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• (9H-fluoren-9-yl)methyl(1-((6-(tert-butoxycarbonyl)amino-1-((4-methyl-2-oxo-1,2-dihydroquinolin-7-yl)amino)-1-oxohexan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate
• Anticonvulsants
• Carbamates
• Dipeptides
• Quinolones
• Receptor, Galanin, Type 1
• Receptor, Galanin, Type 2
• Recombinant Proteins
• Pilocarpine

Topics

• Allosteric Regulation
• Animals
• Anticonvulsants (pharmacology)
• Carbamates (pharmacology)
• Cell Line
• Dipeptides (pharmacology)
• Disease Models, Animal
• Electroshock
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Pilocarpine (toxicity)
• Quinolones (pharmacology)
• Rats
• Rats, Wistar
• Receptor, Galanin, Type 1 (metabolism)
• Receptor, Galanin, Type 2 (agonists, metabolism)
• Recombinant Proteins (agonists, metabolism)
• Seizures (drug therapy, etiology)
• Signal Transduction (drug effects)
• Status Epilepticus (chemically induced, drug therapy)