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Anticonvulsant activity of a nonpeptide galanin receptor agonist

Academic Article
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Overview

authors

  • Saar, K.
  • Mazarati, A. M.
  • Mahlapuu, R.
  • Hallnemo, G.
  • Soomets, U.
  • Kilk, K.
  • Hellberg, S.
  • Pooga, M.
  • Tolf, B. R.
  • Shi, T. S.
  • Hokfelt, T.
  • Wasterlain, C.
  • Bartfai, Tamas
  • Langel, Ülo

publication date

  • May 2002

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • 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.

subject areas

  • Adenylyl Cyclase Inhibitors
  • Animals
  • Anticonvulsants
  • Coumarins
  • Disease Models, Animal
  • Hippocampus
  • Ligands
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Structure
  • Oligodeoxyribonucleotides, Antisense
  • Peptides
  • Rats
  • Rats, Wistar
  • Receptor, Galanin, Type 1
  • Receptors, Galanin
  • Receptors, Neuropeptide
  • Seizures
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Identity

PubMed Central ID

  • PMC124541

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.102163499

PubMed ID

  • 12011470
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Additional Document Info

start page

  • 7136

end page

  • 7141

volume

  • 99

issue

  • 10

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