Over 30% of the 50 million people who are affected by epilepsy do not have their seizures adequately controlled, even with the best available medicines. The 29 amino acid neuropeptide, galanin, is a potent endogenous anticonvulsant that activates galanin receptors type 1 (GalR1) and type 2 (GalR2) and a number of groups, including researchers at the Scripps Research Institute, have been trying to develop drugs that mimic the effects of galanin as novel anticonvulsants. Galnon is an example of a systemically active nonpeptide galanin receptor ligand with affinity for the three galanin receptors which has been shown to reduce seizures in animal models. The Scripps team have now identified a compound that acts appears to act as a selective positive allosteric modulator of the galanin receptor type 2 (GalR2) which they hope will have a reduced potential for side effects compared with galnon. The compound, CYM2503, potentiated the effects of galanin in cells stably expressing the GalR2 receptor, but had no detectable affinity for the galanin binding site. In rodent models of epilepsy, intraperitoneal administration of CYM2503 increased the time to seizure, reduced the duration of seizures, and increased survival rate at 24 h.
The study is published in the Proceedings of the National Academy of Sciences.