oa Editorial [Hot topic: G-Protein Coupled Receptors: Drug Targets of Key Importance (Guest Editors: Luca Piali and Christoph Boss)]

As guest editors of this thematic issue of Current Topics in Medicinal Chemistry focusing on “Deorphanized GPCRs in Medicinal Chemistry and Drug Discovery” we would like to thank all the contributors for their support and the submission of excellent articles to important key aspects of GPCR-research. Many medically significant biological processes are mediated by proteins participating in signal transduction pathways that involve Gproteins and their receptors the so called G-protein coupled receptors (GPCRs). These receptors consist of 7 trans-membrane helices and the extracellular N-terminal loop as well as the intracellular C-terminal loop being responsible for the interaction with the G-proteins. The active site where binding to the endogenous ligand as well as to exogenous agonists or antagonists takes place, is located in the membrane and is geometrically designed by few specific features of the trans-membrane helices. The collection of reviews starts with an insightful survey of the role of corticotropin-releasing factor (CRF) in depression and other mood disorders. After a description of the molecular and anatomical elements of the corticotropin releasing hormone system, Nemeroff and colleagues revisit the discovery story of this intriguing system and summarize the current knowledge of the role of this GPCR-binding molecule in depression, early life stress and the sustained impact of early life stress on the CRF system as a whole. They finish with a review of our current understanding of the function of the receptor system, which analyzes gain- or loss-of function studies and ends with current pharmacological attempts and trials to modulate the disease pathology of depression, anxiety and other stress response. It then goes on with an article on three orphan GPCRs which are structurally related with a putative function in inflammation, EBI2, GPR18 and GPR17. The group of Rosenkilde et al. has been intimately involved in the discovery and initial characterization of these three receptors and lay out the current, still fragmented and sometimes controversial, status of our knowledge on these receptors. While there is currently no pharmacological tool-compound to target the receptors, the authors provide the evidence for a rationale why a drug development program might be fruitful. The third review by Serhan and colleagues introduces the reader to a fairly new and as yet pharmacologically little explored concept of “resolution of inflammation”. Rather than assuming that the inflammatory process simply wanes-off with time the authors have been identifying active resolution signaling mechanisms mediated by lipid-binding GPCRs. This whole new and fascinating arena of “resolution pharmacology” is exemplified with three GPCR families, those binding Lipoxins, those binding Resolvins and the so far least characterized protectins. The article integrates both an authoritative overview and an insight into the first-hand discovery story of these receptor systems. Article number 4 by Lindsley et al. summarizes and evaluates recent efforts in the field of histamine H3 receptor antagonists and inverse agonists and discusses potential therapeutic uses of such compounds for the treatment of pathologies involving neurotransmitters. The article as well summarizes the medicinal chemistry status in this important field of pharmaceutical research. The subsequent article by Leurs et al. reflects the aspect of histamine H4 receptor agonism and antagonism and describes the successful design of selective H4 receptor agonists as well as antagonists, the efforts to analyze receptor ligand interactions with site directed mutagenesis experiments and gives an insight into structure-activity- relationship data of different chemical classes of receptor ligands. The following article written by Rocher et al. abstracts the recent efforts to find negative allosteric modulators of the metabotropic glutamate receptor 5 and delineates the potential of these agents for the treatment of CNS (anxiety, depression or neurodegeneration) as well as non-CNS disorders with a focus on gastro-esophageal acid reflux disease. Rocher et al. deliver a comprehensive summary over the most important medicinal chemistry efforts within this domain of potentially therapeutically useful molecules. The next article by Coleman et al. concentrates mainly on Merck's efforts towards the identification of potent dual orexin-1 / orexin-2 receptor antagonists for the treatment of diverse aspects of sleep disorders focusing on primary insomnia. The article is an excellent summary of a significant amount of medicinal chemistry work and gives a very interesting insight into strategies to design and optimize dual orexin receptor antagonists. The last article of this thematic volume by Bolli and co-workers is an extensive and insightful review of the current landscape of the discovery and development of Sphingosine-1-phosphate (S1P) receptor agonists, which have received a lot of attention recently as a nonselective S1P receptor agonist developed by Novartis (FTY720) is likely to become the first oral treatment for multiple sclerosis. As a consequence, the review focuses on agonists for the receptor S1P1, the target responsible for the reduction of blood lymphocyte count and therefore for efficacy in autoimmune disease. After an introduction to the biology of S1P itself, the remainder of the article concentrates on the medicinal chemistry efforts targeting S1P1, that have been described either in peer-reviewed publications or in the patent literature. Truly, a who-is-who of the S1P1 agonist field. It was a very interesting if not exciting endeavor to put this thematic issue of “Current Topics in Medicinal Chemistry” together. The result is of excellent quality due to the very important contributions of all the authors. We are convinced that to contribute to the field of GPCR-research is of key importance for the pharmaceutical community to deliver efficacious and safe treatments for severe diseases in the near future.