Novel Compounds for the Treatment of Memory Disorders

We have generated a monoclonal antibody, B6B21, and have shown that it significantlyenhances acquisition rates in hippocampus-dependent trace eyeblink conditioning in rabbits, halving thenumber of trials required to reach 80% conditioned responses. Previous studies, with a variety of modelsystems, have shown that B6B21 acts as a partial ago mst at the glycine site of the N-methyl-D-aspart-ate receptor (NMDAR). NMDAR play a central role in learning, memory loss due to aging andAlzheimer's disease, modulation of pain perception, and possibly schizophrenia. Glutamate excitotoxicity,mediated by overactive NMDAR, is one of the principal ways that neurons are damaged by stroke. Thelong-term goal of Neurotherapeutics, Inc. is to develop a memory enhancer by using B6B21 as atemplate to create peptides and/or mimetics that will be more efficacious than the original antibody, andcross the blood-brain barrier. This will be accomplished by cloning and sequencing the variable heavyregion of B6B21. This Phase I application proposes to test B6B21 in aged rabbits using thehippocampus-dependent, trace conditioning paradigm. We must establish concentration-dependence andefficacy in memory-impaired mammals (rabbits) before we can segue into structure-function studies withmodified antibody.