The discovery of new anesthetics by targeting GABAA receptors

Abstract

Many of the general anesthetics, currently used in clinical practice, work through interactions with GABAA receptors. The last 2 decades has witnessed substantial progress in defining the molecular mechanisms by which general anesthetics interact with GABAA receptor sites. However, despite progress in the basic scientific understanding of the mechanism of action of general anesthetics, introduction of novel general anesthetic agents into clinical practice has proven quite challenging. Areas covered: The focus of this review is on the potential for translating basic science advances into the design of new and improved anesthetics. The authors review general anesthetics in current practice as well as anesthetic drug candidates in development and discuss the potential for novel anesthetic drug development. Expert opinion: Opportunities for the discovery of new anesthetics include: computational-based ligand-design, structure-based design, re-exploration of old structureactivity data, absorption, distribution, metabolism, excretion and toxicity predictions and high-throughput screening. The authors believe a lack of high-resolution three-dimensional structures of mammalian GABAA receptors remains a significant limiting factor in structure-based anesthetic drug design. © 2011 Informa UK, Ltd.