Novel N-Methylated 8-Oxoisoguanines from Pacific Sponges with Diverse Neuroactivities

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.

Recent progress in neuroactive marine natural products

“…257 This is the first example of simple purine derivative with opioid receptor activity. It remains to be determined if the compounds are agonists or antagonists.…”

“…Recently, 8-oxoisoguanines of sponge origin were found to have diverse neuronal activities. 257 1,9-dimethyl-8-oxoisoguanine ( 202 ) elicited potent convulsant behaviors in mice after i.c.v. injection, which likely arose from a reduction in inhibitory signaling in the CNS.…”

Marine Alkylpurines: A Promising Group of Bioactive Marine Natural Products

“…and Amphimedon sp. [ 38 ]. These isomers were identified as 1,9-dimethyl-8-oxoisoguanine, 29 , 1,3-dimethyl-8-oxoisoguanine, 30 , 3,9-dimethyl-8-oxoisoguanine, 31 , and 9-methyl-8-oxoisoguanine, 32 ( Figure 8 ).…”

“…These 8-oxoisoguanines seemed to be responsible for the convulsant effect observed for the aqueous extracts of these Palauan sponges, being potential new neuropharmacological agents. Indeed, 1,9-dimethyl-8-oxoisoguanine, 29 , induced convulsions in a dose-dependent manner through inhibition of neuronal GABAergic transmission [ 38 ].…”

Marine Pharmacology in 2009–2011: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis, and Antiviral Activities; Affecting the Immune and Nervous Systems, and other Miscellaneous Mechanisms of Action

“…Inutsuka and colleagues contributed novel molecular studies on the effect of calyculin A ( 149 ) on neurons, demonstrating that rapid rat hippocampal neuron neurite retraction (apparent IC 50 = 100 mM) induced by the toxin was dependent on actin filament polymerization or myosin II motor, yet independent of the microtubule polymerization status, and perhaps resulted from dephosphorylation of myosin light chain kinase [139]. Sakurada and colleagues reported that the novel Palauan sponge Cribrochalina olemda purine ( 150 ), which elicited convulsions upon intracerebroventricular injections in mice (4 nM/mouse), inhibited GABAergic transmission in hippocampal neurons [140]. Noteworthy was the author’s observation that this marine purine was “closely related in structure to endogenous neurosignaling molecules and commonly used CNS stimulants”.…”