The molecular diversity of marine secondary metabolites has been recognized for a number of years, and classic marine-derived excitatory amino acids (EAAs) such as kainic and domoic acid have been indispensable tools in neurobiological research. The recent discovery of the sponge-derived EAA dysiherbaine (DH, 1), a novel di-amino di-acid glutamate analogue with potent convulsant activity, underscores the relatively untapped potential of marine organisms to serve as sources of EAAs with unique structures and activities . DH (1) has a number of pharmacological actions but binds with highest affinity to kainate receptors, a sub-family of non-N-methyl-D-aspartate (non-NMDA)-type GluRs, which are also the molecular targets of other potent EAA convulsants like domoic acid. The high affinity and selectivity of 1 towards certain kainate receptor subtypes made it a useful tool for exploring aspects of the biophysical function of these ion channels . In combination with chemical syntheses and neurophysiological techniques, we have shown that 1 and its structural analogues can serve as unique biophysical and physiological probes of GluR function . Current studies have begun to elucidate the critical moieties on 1 that confer activity and selectivity. We anticipate that 1 will serve as a useful template upon which to build molecules with novel pharmacological actions and potential therapeutic applications. In this review, we describe the chemical, pharmacological and behavioral profile of 1 and closely related analogues, with a particular emphasis on their actions on iGluRs, a family of ligand-gated ion channel critical for excitatory neurotransmission in the mammalian brain.
|Central Nervous System Agents in Medicinal Chemistry
|出版済み - 2006