GalR2-positive allosteric modulator exhibits anticonvulsant effects in animal models.
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.
Lu
Xiaoying
X
Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, CA 92037, USA. xiaoying@scripps.edu
Roberts
Edward
E
Xia
Fengcheng
F
Sanchez-Alavez
Manuel
M
Liu
Tianyu
T
Baldwin
Roger
R
Wu
Stephanie
S
Chang
James
J
Wasterlain
Claude G
CG
Bartfai
Tamas
T
D000494:Allosteric Regulation; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D002460:Cell Line; D004151:Dipeptides / Q000494:pharmacology*; D004195:Disease Models, Animal; D004597:Electroshock; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010862:Pilocarpine / Q000633:toxicity; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044091:Receptor, Galanin, Type 1 / Q000378:metabolism; D044092:Receptor, Galanin, Type 2 / Q000819:agonists* / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy / Q000209:etiology; D015398:Signal Transduction / Q000187:drug effects; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy
C552254:(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; D000927:Anticonvulsants; D002219:Carbamates; D004151:Dipeptides; D015363:Quinolones; D044091:Receptor, Galanin, Type 1; D044092:Receptor, Galanin, Type 2; D011994:Recombinant Proteins; D010862:Pilocarpine