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Abstract
Grant Number: 1R03MH084836-01A209 Project Title: High throughput screening of a general anesthetic binding site
PI Information: Name Title ECKENHOFF, RODERIC G. roderic.eckenhoff@uphs.upenn.edu PROFESSOR Abstract: DESCRIPTION (provided by applicant): We propose a high throughput screen at NCGC for general anesthetics based on binding to a well characterized site in a GABAA mimic, apoferritin. The assay is based on competition of compounds with enhanced 1-aminoanthracene fluorescence. The assay has been taken to a 1536-well format, and shows excellent signal: background and signal: noise ratios, and when tested with positive control compounds, achieves Z' factors better than 0.8. The LOPAC 1280 set has been screened which resulted in retrieval of the only know general anesthetic in the library, and several other compounds most of which were validated by ITC. After primary screen, a novel computational filter will be applied, followed by SAR, clustering and triage of actives in collaboration with NCGC. Validation screens will use ITC to confirm and extend the HTS IC50 values. In addition to providing several probe compounds for further development, this project is likely to provide useful laboratory reagents and inform protein-ligand chemistry. PUBLIC HEALTH RELEVANCE: General anesthetics are used in over 40 million patients in the US each year, and, although known to have worrisome side effects, have recently been discovered to have durable cognitive effects. New and more specific drugs are required to avoid these side effects. We propose a high throughput screen of the molecular library compounds for binding to a favorable anesthetic site in order to generate probe compounds for further development as safe general anesthetics.
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Institution: UNIVERSITY OF PENNSYLVANIA 3451 Walnut Street PHILADELPHIA, PA 19104 Fiscal Year: 2009 Department: ANESTHESIOLOGY AND CRITICAL CARE Project Start: 20-JUL-2009 Project End: 30-JUN-2010 ICD: NATIONAL INSTITUTE OF MENTAL HEALTH IRG: ZRG1