The kainoids are a class of both naturally occurring and synthetic pyrrolidine dicarboxylates with excitatory and excitotoxic activity on the mammalian central nervous system. Representative of this class of compounds is domoic acid. Exposure to this marine neurotoxin induces a syndrome known as Amnesic Shellfish Poisoning. The kainoids exhibit nanomolar binding affinities (kd's) for a subclass of ionotropic glutamate receptors known as the kainate receptors (high and low affinity types). Furthermore these compounds activate two subclasses of glutamate gated ion channels at micromolar concentrations (Kainate and AMPA) and act as inhibitors of glutamate uptake with varying degrees of selectivities and potencies. The kainoids are generally thought of as conformationally restricted glutamate analogs and it is believed that their agonist properties are a result of being fixed into the preferred binding conformation. Conformational analysis of kainic acid indicates that the kainate ring is actually quite flexible and may adopt as many as ten different conformations within a 25kJ/mol energetic window. It is believed that the flexibility of the kainate ring imparts its ability to activate multiple receptor subtypes. The synthesis a number of kainate analogs which are conformationally fixed and that mimic the conformations available to the kainate ring are proposed. These compounds will then be screened for their affinity for both kainate and AMPA receptor subtypes. Receptor binding assays will be followed by functional assays, monitoring calcium flux and inhibition of glutamate uptake. In this way, the PI proposes to identify the preferred binding conformation of the kainoids at the both the kainate sites and the AMPA site and to develop selective agonists for the kainate receptors. The availability of selective agonists for the various glutamate receptor subtypes should allow the identification of the specific receptor function and uncover the precise mechanism of action of domoic acid poisoning.
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