Anticonvulsant activity of a nonpeptide galanin receptor agonist.
Galanin is a neuropeptide with a wide variety of biological functions, including that of a strong endogenous anticonvulsant. No nonpeptide ligands, capable of activating galanin receptors, are available today. Based on known pharmacophores of galanin, a combinatorial library was designed, synthesized, and screened at the rat hippocampal galanin receptor. A low molecular weight galanin receptor agonist, 7-((9-fluorenylmethoxycarbonyl)cyclohexylalanyllysyl)amino-4-methylcoumarin (galnon) was found to displace (125)I-galanin with micromolar affinity at Bowes cellular and rat hippocampal membranes. Autoradiographic binding assay on rat spinal cord sections confirmed the ability of galnon to displace (125)I-galanin from its binding sites. Galnon inhibited adenylate cyclase activity, suggesting an agonist action at galanin receptors. When injected i.p. galnon reduced the severity and increased the latency of pentylenetetrazole-induced seizures in mice and reversed the proconvulsant effects of the galanin receptor antagonist M35, injected into a lateral ventricle. Intrahippocampal injection of galnon also shortened the duration of self-sustaining status epilepticus in rats, confirming its agonist properties in vivo. Pretreatment of rats with antisense peptide nucleic acid targeted to galanin receptor type 1 mRNA abolished the effect of galnon, suggesting mediation of its anticonvulsant properties through this receptor subtype. These findings introduce a systemically active nonpeptide galanin agonist anticonvulsant.
Saar
Külliki
K
Department of Neurochemistry and Neurotoxicology, Stockholm University, SE-10691 Stockholm, Sweden.
Mazarati
Andrey M
AM
Mahlapuu
Riina
R
Hallnemo
Gerd
G
Soomets
Ursel
U
Kilk
Kalle
K
Hellberg
Sven
S
Pooga
Margus
M
Tolf
Bo-Ragnar
BR
Shi
Tiejun S
TS
Hökfelt
Tomas
T
Wasterlain
Claude
C
Bartfai
Tamas
T
Langel
Ulo
U
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D020319:Oligodeoxyribonucleotides, Antisense; D010455:Peptides; D051381:Rats; D017208:Rats, Wistar; D044091:Receptor, Galanin, Type 1; D044088:Receptors, Galanin; D018013:Receptors, Neuropeptide / Q000819:agonists*; D012640:Seizures / Q000188:drug therapy
C456547:7-((9-fluorenylmethoxycarbonyl)cyclohexylalanyllysyl)amino-4-methylcoumarin; D000067956:Adenylyl Cyclase Inhibitors; D000927:Anticonvulsants; D003374:Coumarins; D008024:Ligands; D020319:Oligodeoxyribonucleotides, Antisense; D010455:Peptides; D044091:Receptor, Galanin, Type 1; D044088:Receptors, Galanin; D018013:Receptors, Neuropeptide