The goal of this research effort is to identify new pharmacological agents that act on ionotropic glutamatereceptors, the primary mediators of excitatory synaptic transmission in the mammalian brain. As well, weseek to understand how such molecules interact with the binding domains of their target receptors togenerate selective pharmacological profiles. The research program is based on the premise thatpharmacologically and clinically relevant neuroactive molecules can be isolated and characterized frommarine 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 ofits extremely high affinity for kainate receptors (KARs). Furthermore, small modifications of the DH structureswitched its activity from that of a potent agonist to a selective antagonist, suggesting that DH could serve astemplate from which to generate selective KAR antagonists with unique pharmacological profiles. Suchantagonists could be of relevance to both basic and clinical research, because few selective KARantagonists have been identified and compounds with this pharmacological profile have potential therapeuticefficacy 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 avariety of activities and affinity profiles on kainate receptors. Those antagonists with novel subunit-selectivitywill 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 KARsubunits and DH-related ligands. The results will inform the generation of new synthetic ligands designed tohave particular pharmacological activities on KARs. Third, we will isolate and characterize the activeprinciples in a bioactive sponge extract that potentiates AMPA and KAR currents. This activity is similar to ofAMPA receptor modulators currently under investigation for efficacy in prevention of cognitive decline. Insummary, these projects have the shared goal of identification and pharmacological analysis oftherapeutically promising molecules for treatment of neurological diseases.
|Effective start/end date||7/1/02 → 6/30/07|
- National Institute of Neurological Disorders and Stroke (3 R01 NS044322-05S1)