NMDA Receptor Antagonists That Spare LTP

The N-methyl-D-aspartate (NMDA) subtype of glutamate receptor has been implicated in avariety of neurological pathologies including ischemic brain damage (stroke), head trauma, spinal cordinjury, epilepsy, neurodegenerative disorders such as Alzheimer's Disease, and hyperalgesic states. Thedevelopment of NMDA antagonists as therapeutants, however, has been hampered by the occurrenceof deleterious side effects such as the impairment of cognition. Studies in our laboratory have identifieda new class of NMDA antagonists termed arylalkylamines which act at a unique site and by a novelmechanism. We have discovered in preliminary experiments that arylalkylamines fail to inhibit theinduction of tetanization-induced long-term potentiation (LTP) at the Schaffer collateral-CAl pyramidalcell synapse and, therefore, are the first class of potent and selective NMDA antagonists which do notblock LTP induction in this pathway. As LTP may represent the cellular basis for certain forms oflearning and memory, this finding suggests that drugs developed from arylalkylamines may lack effectson cognition. These 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 arylalkylaminesas lead structures for the development of a new class of therapeutants for neurological disordersdistinguished by their decreased propensity to impair cognition.