The N-methyl-D-aspartate (NMDA) receptor appears to be an excellent target for the development of cognitive enhancers. We have generated a monoclonal antibody, B6B21, and have shown that it significantly enhances acquisition rates in hippocampus- dependent trace eyeblink conditioning and acts as a partial agonist at the glycine site of the NMDA receptor. We now have cloned and sequenced the hypervariable regions of the light chain of B6B21. From this information, we have generated and patented a family of biologically active peptides. From these a lead compound has been identified: the tetrapeptide NT-13 that mimics B6B21 pharmacologically and physiologically and crosses the blood-brain barrier. We propose to evaluate the cognitive enhancing properties of NT-13 by administering the compound I.V. to adult rats and subjecting them to an ensemble of learning paradigms: trace eyeblink conditioning, trace fear conditioning, and Morris water maze. In Phase II, receptor subtype specificity, toxicity, tissue distribution, and pharmacokinetics will be assessed. These studies, taken together, should provide sufficient data to take NT-13 or a non-peptide mimetic to clinical trials via a joint venture.
1) Aged individuals with benign senescent forgetfulness (Bazargan and Bargre, 1994; Glasser, et al., 1994): up to 20 million persons; 2) Individuals with Alzheimer's disease (Cummings and Benson, 1983; Wang, 1977): 2.5 and 4 million persons; 3) Children and adults with learning disabilities (McDermott, 1994): 1.5 to 2 million people; 4) Normal individuals who might seek to augment their learning abilities: 100 plus million persons.
| Stanton, Patric K; Potter, Pamela E; Aguilar, Jennifer et al. (2009) Neuroprotection by a novel NMDAR functional glycine site partial agonist, GLYX-13. Neuroreport 20:1193-7 |
| Moskal, Joseph R; Kuo, Amy G; Weiss, Craig et al. (2005) GLYX-13: a monoclonal antibody-derived peptide that acts as an N-methyl-D-aspartate receptor modulator. Neuropharmacology 49:1077-87 |
