Novel N -methylated 8-oxoisoguanines from pacific sponges with diverse neuroactivities

Tsuyoshi Sakurada, Martin B. Gill, Shanti Frausto, Bryan Copits, Keiichi Noguchi, Keiko Shimamoto, Geoffrey T. Swanson, Ryuichi Sakai

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Marine organisms have yielded a variety of metabolites with neuropharmacological applications. Here we describe the isolation and pharmacological characterization of four novel, neurologically active purines 1-4, isolated from Haplosclerida sponges collected in the Republic of Palau. The structures were determined by analyses of spectral and X-ray data. Compound 1 induced convulsions upon intracerebroventricular injection into mice, with a CD50 value of 2.4 nmol/mouse. Purines 2-4 were active in mouse bioassays at higher doses. The seizurogenic activity of 1 was correlated with inhibition of neuronal GABAergic transmission, with only a modest impact on excitatory signaling, in electrophysiological recordings from hippocampal neurons. Despite having a purine template structure, the inhibitory activity of 1 was not prevented by a nonselective adenosine receptor antagonist. Thus, 1 represents a novel substituted purine that elicits convulsions through its actions on inhibitory neurotransmission. These 8-oxoisoguanine analogs comprise a new family of compounds closely related in structure to endogenous neurosignaling molecules and commonly used CNS stimulants.

Original languageEnglish (US)
Pages (from-to)6089-6099
Number of pages11
JournalJournal of Medicinal Chemistry
Volume53
Issue number16
DOIs
StatePublished - Aug 26 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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