Anticonvulsant Activity of a Nonpeptide Galanin Receptor Agonist

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2002 May 16

PMID 12011470

Citations 38

Authors

Kulliki Saar

Andrey M Mazarati

Riina Mahlapuu

Gerd Hallnemo

Ursel Soomets

Kalle Kilk

Sven Hellberg

Margus Pooga

Bo-Ragnar Tolf

Tiejun S Shi

Tomas Hokfelt

Claude Wasterlain

Tamas Bartfai

Ulo Langel

Affiliations

Soon will be listed here.

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.

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