The goal of this research effort is to identify new pharmacological agents that act on ionotropic glutamate receptors, the primary mediators of excitatory synaptic transmission in the mammalian brain. As well, we seek to understand how such molecules interact with the binding domains of their target receptors to generate selective pharmacological profiles. The research program is based on the premise that pharmacologically and clinically relevant neuroactive molecules can be isolated and characterized from marine sponges. We previously described the most potent seizurogenic amino acid yet characterized, dysiherbaine (DH), which was purified from a marine sponge extract. DH is a potent convulsant by virtue of its extremely high affinity for kainate receptors (KARs). Furthermore, small modifications of the DH structure switched its activity from that of a potent agonist to a selective antagonist, suggesting that DH could serve as template from which to generate selective KAR antagonists with unique pharmacological profiles. Such antagonists could be of relevance to both basic and clinical research, because few selective KAR antagonists have been identified and compounds with this pharmacological profile have potential therapeutic efficacy for treatment of pain and epilepsy. To pursue this goal we first will screen novel analogs of DH for activity as selective KAR antagonists. Preliminary results demonstrate that synthetic stereoisomers and other analogs of dysiherbaine have a variety of activities and affinity profiles on kainate receptors. Those antagonists with novel subunit-selectivity will be tested for activity on synaptic receptors in brain slice preparations. Second, we will carry out structure-function studies to test specific hypotheses regarding the molecular interactions between different KAR subunits and DH-related ligands. The results will inform the generation of new synthetic ligands designed to have particular pharmacological activities on KARs. Third, we will isolate and characterize the active principles in a bioactive sponge extract that potentiates AMPA and KAR currents. This activity is similar to that of AMPA receptor modulators currently under investigation for efficacy in prevention of cognitive decline. In summary, these projects have the shared goal of identification and pharmacological analysis of therapeutically promising molecules for treatment of neurological diseases. ? ?
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