Preface [Hot Topic: G Protein-Coupled Receptors (GPCRs) (Executive Editors: P.M. Sexton and A. Christopoulos)]

G protein-coupled receptors (GPCRs) comprise the largest class of cell surface receptor proteins and represent the major targets for currently used therapeutic agents. This issue of Current Pharmaceutical Design is the inaugural publication of a series devoted to GPCRs that will broadly deal with the utility of this receptor class in drug development. This issue contains invited review articles from preeminent researchers in the field. In their article, Graeme Milligan and colleagues [1] explore the utility of GPCR-fusion proteins in drug discovery. The paper discusses the wide range of potentially useful fusion partners, from fluorescent proteins and reporter genes through to specific G proteins, and how these can be used in assays of receptor activation and other aspects of receptor function including internalization and interaction with other proteins. The article also looks at the use of modified proteins that can engender increased constitutive receptor activity and how these may be useful for screening for inverse agonists. The article of Arthur Christopoulos and colleagues [2] looks at the potential of allosteric drugs acting at GPCRs. The paper discusses the potential therapeutic advantages of this class of drugs, some of the difficulties that can be encountered in drug screening and experimental and analytical methods that can be used to specifically identify drugs that act allosterically. In his article, Bill Messer [3] examines the development and utility of bivalent ligands as drugs for GPCRs. The paper discusses how these compounds can provide novel drug leads, both agonist and antagonist, that have improved receptor subtype specificity while maintaining high receptor affinity. The final two articles are comprehensive analyses of structural and functional aspects of small molecule compounds acting at either the adenosine A1 receptor or the CCR5 and CXCR4 chemokine receptors. Sally Hutchinson and Peter Scammells [4] explore the development and utility of agonist and partial agonist drugs that target the A1 receptor, including discussion of alternative pharmacophore models. The article of Christoph Seibert and Tom Sakmar [5] discusses antagonists of the CCR5 and CXCR4 receptors as promising new anti-HIV drugs and includes recent insights on how the small molecule compounds interact with each of these receptors. We are grateful to each of our contributors for their effort and also their patience in the preparation of this inaugural issue.