Dysiherbaine:  A New Neurotoxic Amino Acid from the Micronesian Marine Sponge Dysidea herbacea

A new amino acid, dysiherbaine (1), was isolated from a Micronesian sponge Dysidea herbacea. The structure was determined by using FABMS, ESIMS, FABMS/CID/MS, and one- and two-dimensional NMR experiments of 1 and its dimethyl derivative 3 to be a novel diamino dicarboxylic acid, which consisted of a cis-fused hexahydrofuro[3,2-b]pyran ring substituted with a 3-[2-aminopropanoic acid] side chain. The relative configuration of the bicyclic portion of 1 was determined by 3JH,H analysis and difference NOE experiments, and that of the acyclic side chain was assigned by additional 2,3JC,H analysis, measured by hetero half-filtered TOCSY (HETLOC) and phase sensitive HMBC experiments. Systemic administration of 1 induced neurotoxic symptoms in mice which were reminiscent of neuroexcitatory amino acids such as domoic acid. Dysiherbaine inhibited bindings of [3H]-kainic acid (KA) and [3H]-1-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), but not [3H]CGS-19755, an N-methyl-d-asparatic acid (NMDA) receptor antagonist, on rat brain synaptic membranes, suggesting that 1 is a selective agonist of non-NMDA type glutamate receptors in the central nervous system.