Our lab focuses on the 13-amino-acid neuropeptide neurotensin, which was first discovered in the brain more than 30 years ago. Evidence suggests that brains affected by Alzheimer's disease have neurotensin deficits in areas involved with memory function. Neurotensin also may be involved in Parkinson's disease and schizophrenia. Our goal is to develop new drugs that stimulate brain receptors for neurotensin in an effort to reverse or stop the progression of these neuropsychiatric diseases.
A receptor is a highly specialized protein that usually resides on the surface of cells to bind specific molecules such as neurotensin. Nerve cells and other types of cells communicate with one another by releasing chemical messengers that activate other cells by binding to their target receptors. This laboratory has molecularly cloned the human gene for the neurotensin receptor, subtype 1, and has been able to replicate it in non-human host cells grown in the laboratory. Cell lines containing this gene are able to produce the human neurotensin receptor, obviating the need to obtain human brain tissue at autopsy as a source of this receptor. The availability of an exact copy of this gene has simplified both the study of the neurotensin receptor and the development of potential drugs that activate it.
Neurotensin consists of 13 amino acids. Dr. Richelson and others have clearly shown that the last six amino acids of this peptide are all that is needed to activate potently neurotensin receptors. Dr. Richelson's group has synthesized analogs of the neurotensin fragment, containing unnatural amino acids. By introducing amino acids not found naturally in the body into the structure of the peptide, it becomes more resistant to being degraded by peptidases. A collaborator at Mayo Clinic Rochester, Dr. Daniel McCormick, Co-Director of the Mayo Proteomics Research Center, has been able to provide a large number of such peptides. Dr. Richelson's group has tested these compounds for their abilities to bind and to stimulate the human neurotensin receptor, subtype 1.
A number of promising compounds have come from these studies. Several of these compounds are able to pass a barrier, called the blood-brain barrier that prevents many types of molecules, including peptides, from entering the brain. This is a mechanism to protect the brain from potential toxins that are normally present in the blood. A U.S. Patent (#6,214,790) was recently issued on these peptides. In studies with laboratory animals (mice and rats), these peptides cause effects that could only result from stimulation of neurotensin receptors in brain. Additionally, the data suggest that these peptides may have therapeutic effects in Parkinson's disease and in schizophrenia. Preclinical toxicology studies with one of these compounds, NT69L, are underway to determine whether it can be tested in humans.
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