Novel N-methylated 8-oxoisoguanines from Pacific sponges with diverse neuroactivities.
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.
Sakurada
Tsuyoshi
T
Faculty of Fisheries Sciences, Hokkaido University, Hakodate 041-8611, Japan.
Gill
Martin B
MB
Frausto
Shanti
S
Copits
Bryan
B
Noguchi
Keiichi
K
Shimamoto
Keiko
K
Swanson
Geoffrey T
GT
Sakai
Ryuichi
R
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002478:Cells, Cultured; D003292:Convulsants / Q000302:isolation & purification* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006147:Guanine / Q000031:analogs & derivatives* / Q000302:isolation & purification* / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D019029:Palau; D018408:Patch-Clamp Techniques; D011161:Porifera / Q000737:chemistry*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
D003292:Convulsants; D011956:Receptors, Cell Surface; D006147:Guanine