Guanine nucleotide-binding protein (G protein)coupled receptors (GPCRs) are integral membrane proteins that mediate the actions of a vast array of endogenous stimuli and represent the major targets for approximately 30% of all medicines on the market [ 1-3] . Due to their ubiquitous cell surface expression, GPCRs are very tractable drug targets. However, GPCR-based drug discovery programs, in common with those of many other targets, suffer from a high attrition rate. This is likely due to two major reasons: (1) an insufficient mechanistic understanding of the relationship between common biological screening assays of GPCR behavior and the actual GPCR therapeutic end point that is being targeted in the drug discovery program; (2) a paucity of highly GPCR subtype -selective ligands. With respect to the former, the growing characterization of the in vivo physiological roles of GPCRs via knockout animals in recent years, as well as a realization of the need to compare multiple indices of GPCR function when screening for drug effects, is promising to make some headway in guiding more informed approaches to appropriate drug screening. With respect to the selectivity issue, this is possibly due to the fact that traditional drug discovery has targeted GPCR orthosteric sites, that is, the natural binding sites for the receptors' endogenous ligands, in

GPCR Molecular Pharmacology and Drug Targeting: Shifting Paradigms and New Directions,

Edited by Annette Gilchrist

Copyright © 2010 John Wiley & Sons, Inc.

the search for novel molecules that either mimic or block the actions of the endogenous ligands. Because orthosteric sites are generally well conserved across different subtypes of a given receptor, chemotypes that target such binding pockets may be expected to lack selectivity if they primarily utilize attachment points common to each subtype of GPCR. However, it is now recognized that many GPCRs possess topographically distinct, allosteric binding sites, and that ligands that bind to these sites offer tremendous potential for more selective and/or effective therapies than conventional orthosteric ligands.

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