Novel therapeutics for learning and memory disorders

DESCRIPTION (provided by applicant): The N-methyl-D-aspartate receptor (NMDAR) is an excellent target for the development of therapeutic cognitive enhancers: of the many targets on this receptor, the glycine co-agonist site appears especially attractive. Previously, a monoclonal antibody, B6B21, was created that acts as a partial agonist at the glycine site of the NMDAR. The hypervariable region of the light chain of B6B21 was cloned and sequenced. Peptides were then synthesized based on this sequence information and screened using rat hippocampal membrane preparations to measure [3H]-MK-801 binding in the presence of 7-chlorokynurenic acid, a glycine site-specific competitive inhibitor of the NMDAR. Peptides that were able to increase [3H]-MK801 binding in a dose-dependent manner under these conditions were named Glyxins. GLYX-13, a tetrapeptide, was found to readily cross the blood-brain barrier and act as a partial agonist when examined pharmacologically and electrophysiologically. When GLYX-13 was administered to rats at 0.5-1.0 mg/kg, i.v., a significant enhancement in learning was observed using a hippocampus-dependent trace eyeblink conditioning paradigm. We propose to extend these studies by evaluating GLYX-13 in a variety of learning paradigms in both young and aged rats. These are the Morris water maze, hippocampus-dependent trace eyeblink conditioning, and T-maze. Long-term potentiation and long-term depression in hippocampal slices will also be examined. We will also compare the bioavailability of GLYX-13 by intravenous, oral, and sub-cutaneous administration. Additionally, we will evaluate availability to the CNS via monitoring GLYX-13 effects on basal and harmaline-induced cerebellar cGMP. This approach will also allow us to define the in vivo agonist and antagonist dose ranges of this partial agonist. While the data obtained to date indicates that the Glyxins are a new class of NMDA-receptor modulators that have therapeutic potential, the studies proposed here are necessary to show that these compounds can be successful in clinical trials.