As the primary excitatory neurotransmitter in the mammalian CNS, L- glutamate signalling is mediated through a combination of at least five classes of receptors. The characterization of these receptors is a topic at the forefront of neuroscience because of their role not only in standard fast excitatory synaptic transmission, but their involvement in more complex neuronal processes, such as development, learning and memory. It appears, however, that the ability of the glutamate system to participate in these aspects of CNS function is balanced by its additional ability to contribute to neuropathology. Thus, many of the same properties that allow these receptors to contribute to intracellular signalling can, when not properly regulated, lead to neuronal injury and the eventual death of the neuron. Such excitotoxicity is thought to underlie the neuronal damage associated with a wide variety of neurological insults and diseases, including, ischemia, anoxia, stroke, hypoglycemia, epilepsy, Huntington's disease, amyotrophic lateral sclerosis, lathyrisms, and Alzheimer's disease. The goal of this project is to provide a better understanding of the interactions between glutamate and its various receptors. There are a large number of conformationally restricted glutamate analogs that exhibit selective binding to specific subpopulations of glutamate receptors, but despite these empirical selectivities, there is not a clear understanding of these interactions at the molecular level. The fact that such selectivities exist implies that glutamate itself binds to each type of receptor in a unique conformation, each of which is mimicked by one or more of the analogs. In order to determine conformational preferences for each receptor type, i.e., optimal positioning of the functional groups and intervening hydrocarbon chain responsible for binding of agonists or antagonists, the rational design of an extensive set of conformationally well-defined analogues is being undertaken. The specific objectives are i) A systematic series of configurationally varied, but conformationally well-defined, enantiomerically pure omega-carboxy-alpha-amino acids will be prepared in order to mimic defined conformations of excitatory acidic amino acids such as L-glutamate. Emphasis will be on compounds that, in effect, restrict rotation about the two central C-C bonds of glutamate, ii) structure/activity studies will be performed to identify the selectivity and potency with which the series of conformationally defined analogues bind to the EAA receptors and transport systems, and iii) molecular modelling will compare known conformations of glutamate, conformations attainable by each analogue, and the results of the structure/activity studies to define the selectivities of the EEA transmitter components and lead to further structural refinements in design and synthesis. The ultimate goal is a complete understanding of agonist and antagonist action at each receptor type, which could ultimately lead to the improved design of CNS drugs.
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