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-CAI 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. These studies will expand on this preliminary finding by (I) 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.Awardee's statement of the potential commercial applications of the research:NMDA receptor antagonists have potential therapeutic utility in neurological disorders (e.g., ischemic brain damage, epilepsy, and neurodegenerative diseases). The development of NMDA antagonists as therapeutants, however, has been hampered by the occurrence of deleterious side effects such as impairment of cognition. Arylalkylamines are potentially the first class of potent and selective NMDA antagonists which do not impair the induction of hippocampal LTP, and thus represent unique lead structures for the development of new therapeutants for neurological disorders distinguished by their decreased propensity to impair cognition.
Thesaurus Terms: N methyl D aspartate receptor, drug screening /evaluation, long term potentiation, neuropharmacology, phenylalkylamine excitatory aminoacid, hippocampus, inhibitor /antagonist, method development, pyramidal cell, spider poison, synapse, tetany laboratory rat, tissue /cell culture National Institute of Neurological Disorders and Stroke (NINDS)
