New Model for Anesthetic Drug Discovery and Development

The assay will allow researchers to look for new anesthetic drugs and new molecular targets for anesthetics, while at the same time creating high-resolution images of the compounds in action, a missing component that has so far hindered anesthetic research. Using transparent albino tadpoles, the researchers were able to follow the fluorophore tag and image it in the brain of the immobilized, living animal. Because the compound is fluorescent, the researchers were able to image the compound in vivo in order to study its physiologic effects. The study was published early online on April 3, 2009, in the Proceedings of the [U.S.] National Academy of Science (PNAS).

"The 1-AMA compound opens up new avenues for identifying the relevant biomolecular targets of general anesthetics," said Ivan J. Dmochowski, Ph.D., an assistant professor in the department of chemistry at Penn. "1-AMA appears to be specific in its binding to proteins and also in its in vivo localization, which should give us the opportunity to determine its mechanism of action. We hope to be able to extend our findings to learn how current general anesthetics, such as propofol, work in human patients.”

"We don't know much about how anesthetics work at a molecular level," said coauthor Roderic Eckenhoff, M.D., a professor of anesthesiology and critical Care at Penn's School of Medicine. "Thus, the development of new anesthetics has become a stagnant field. This new tool will allow for the high-throughput screening of novel drugs."

For many of the most commonly used anesthetic compounds, the molecular mechanisms behind their numbing effects and the way these compounds travel the pathways of the body remain poorly understood or altogether unknown. Because anesthetics bind weakly to their chemical targets--which incidentally may play a role in some of the unintended side effects--searching for new targets in the central nervous system (CNS) is difficult. Anesthetics can bring on potentially harmful, even deadly, side effects for patients including rapid drops in blood pressure and heart rate, nausea, and potentially irreversible cognitive problems, especially in older patients.

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