NMDA RECEPTOR ANTAGONISTS THAT SPARE LTP

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The N-methyl-D-aspartate (NMDA) subtype of glutamate receptor has been implicated in a variety of neurological pathologies including ischemic brain damage (stroke), head trauma, spinal cord injury, epilepsy, neurodegenerative disorders such as Alzheimer's Disease, and hyperalgesic states. The development of NMDA antagonists as therapeutants, however, has been hampered by the occurrence of deleterious side effects such as the impairment of cognition. Studies in our laboratory have identified a new class of NMDA antagonists termed arylalkylamines which act at a unique site and by a novel mechanism. We have discovered in preliminary experiments that arylalkylamines fail to inhibit the induction of tetanization-induced long-term potentiation (LTP) at the Schaffer collateral-CAl pyramidal cell synapse and, therefore, are the first class of potent and selective NMDA antagonists which do not block LTP induction in this pathway. As LTP may represent the cellular basis for certain forms of learning and memory, this finding suggests that drugs developed from arylalkylamines may lack effects on cognition. The proposed studies will expand on this preliminary finding by (1) the examination of other, structurally dissimilar, arylalkylamines, (2) and by the utilization of additional, more physiological, patterns of electrical stimulation to elicit LTP. Such studies will aid in our evaluation of arylalkylamines as lead structures for the development of a new class of therapeutants for neurological disorders distinguished by their decreased propensity to impair cognition.