Discovery of Novel General Anesthetics Using Apoferritin as a Surrogate System

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	NCATS	CHEM-12

Authors

• G Rai
• W Bu
• W. A. Lea
• D Liang
• B Weiser
• V Setola
• C.P. Austin
• A Simeonov
• A Jadhav
• R Eckenhoff
• D. J. Maloney

Abstract

Anesthesia is one of the oldest fields of drug discovery and each year over 40 million patients use anesthetics in the U.S. alone. Despite their frequent use, there are growing concerns over their considerable side effects (e.g. toxicity and neurodegeneration). This has prompted a search for novel anesthetics that may act in a more specific manner. Evidence suggests that general anesthetics exert their functions by directly interacting with specific proteins, such as the GABAA receptor, a ligand-gated ion channel. Due to the limited availability of membrane proteins, especially hetero-oligomers like most GABAA receptors, detailed biochemical characterization has been difficult to perform. As such, current efforts have largely focus on chemical modifications of existing drugs with little attention being made toward de novo drug discovery. However, our lab recently developed a miniaturized fluorescence assay to screen 397,939 compounds, utilizing apoferritin protein as a surrogate for GABAA. Through this effort, a 6-phenylpyridazin-3(2H)-ones series was identified and was subjected to medicinal chemistry optimization and SAR analysis. Lead compounds were profiled in tadpole and mouse models and were found to induce reversible immobilization. Thus, the compounds reported herein represent useful tool molecules for the exploration of general anesthetic mechanisms and further pre-clinical development.

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