GalR2-positive allosteric modulator exhibits anticonvulsant effects in animal models
| Autor: | Stephanie Wu, Xiaoying Lu, Tianyu Liu, Claude G. Wasterlain, Edward Roberts, Tamas Bartfai, Roger A. Baldwin, Fengcheng Xia, Manuel Sanchez-Alavez, James Chang |
|---|---|
| Rok vydání: | 2010 |
| Předmět: | |
| Zdroj: | Proceedings of the National Academy of Sciences. 107:15229-15234 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|