Receptor-Specific Excitatory Amino Acid Analogues

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DESCRIPTION (provided by applicant): This competing renewal will build on the foundation laid during the previous two 4-year grant periods in developing new small molecule ligands for excitatory amino acid (EAA) receptors and transporters. Our intention is to tightly focus our continued efforts on a problem that presents one of the next major challenges in this field, namely the pharmacological differentiation of EAA receptor subtypes that comprise the respective major ionotropic receptor classes, specifically AMPA (comprised of subtypes iGluR1-5), Kainate (subtypes iGluR5-7, KA-1, and KA-2), and NMDA (subtypes NR1-3). We have developed synthesis technology for preparing several structural classes of glutamate analogues (pyrrolidine dicarboxylates, kainates, dysiherbaines, and kaitocephalins) known to be active agonists or antagonists; however, by and large the action of such compounds within the receptor subtypes has yet to be delineated. This is a very important issue because individual members of these subtype groups have been implicated in a growing number of therapeutic areas, including stroke and neurodegenerative diseases, cognitive impairment, epilepsy, and pain. As a result, there is a great deal of interest in the discovery of subtype-selective agonists and antagonists as possible leads for therapeutic agents. We will focus our efforts on these "proven" groups of glutamate ligands, with the expectation that structural modifications will in some cases lead to new compounds with modified subtype selectivities or other novel activities. To accelerate the discovery process, a library approach based on these structural types will be instituted. Because a given pharmacological property (e.g., excitotoxicity) can be a consequence of multiple factors (e.g., subtype-specific agonist potency, desensitization behavior, transport behavior, etc.), the biological screening of new compounds should be as broad as practical. We have therefore teamed up with four outstanding laboratories to screen our analogues and libraries in a wide range of assays: Professor Olivier Civelli (high throughput screening of receptor subtypes for agonist/antagonist activity), Ricardo Miledi (detailed analysis of active compounds in oocyte assays), Professor Gary Lynch (neuronal assays), and Professor Richard Bridges (transport, excitotoxicity, and neuroprotection assays).