Editorial [ Targeting G Protein-Coupled 7TM Receptors in Inflammation Guest Editor: Dr. Trond Ulven ]

Inflammation is the natural immune response of the body to infection or other damage, and is vital to survival. However, occasionally the inflammatory response is out of proportion with the tissue damage, and the survival strategy becomes the problem itself. This is the case with many serious chronic and acute diseases, like allergy and asthma, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and septic shock. It is also established that cancerous diseases, atherosclerosis, metabolic disorders like diabetes mellitus and obesity, and CNS disorders such as multiple sclerosis, Alzheimer's disease and stroke, involve important inflammatory components. Even if progress has been made, it is clear that inflammatory conditions at large still represent a formidable therapeutic challenge, and it appears safe to forecast that this will continue to occupy the pharmaceutical industry and those dedicated to drug discovery into the future. On a molecular level, the inflammatory response is highly complex, involving a vast array of messenger molecules interacting with enzymes and receptors of virtually every class, directing recruitment of immune cells to eliminate the source of infection and recover the healthy state. Indeed, absence of inflammation also involves an active immune system and a balance between the inflammatory messengers, which together with the inherent redundancy of the system makes therapeutic intervention a considerable challenge [1]. A recent issue of this journal dealt with new approaches to treatment of inflammatory disorders, and discussed various molecular targets, including synthases, kinases, nuclear receptors, and targets within the intracellular secretory pathway. The G protein-coupled seven-transmembrane receptors, commonly known as GPCRs, heptahelical receptors or 7TM receptors, make up a large family of cell surface receptors which are found on all cell types in the body and are implicated in virtually every physiological process. Comprising about 200 members with known endogenous ligands in addition to numerous sensory and orphan receptors, the 7TM protein superfamily has proven highly suitable as drug targets, with a substantial fraction of all marketed drugs exerting their action through members of this receptor superfamily. The receptors share a number of characteristic features, including an extracellular N-terminal, seven transmembrane α-helical segments, an intracellular Cterminal, and the ability to activate heterotrimeric G proteins. Despite their common architecture, the 7TM receptors act as cell surface receptors for highly diverse endogenous molecules, including large proteins and small peptides, monoamines, nucleosides, and lipids. Inflammatory mediators encompass a corresponding structural diversity, and the contributions in this issue reflect the variety of these messenger molecules as well as the diversity of endogenous 7TM receptor ligands. Chemokines are a family of 8-12 kDa proteins which play a crucial role in directing leukocytes to the site of inflammation through activation of specific 7TM receptors on the cell surfaces. In the first article in this issue, Rosenkilde and Schwartz give an introduction to chemokines and their receptors. They highlight a specific glutamic acid residue in transmembrane segment VII which is highly conserved throughout the chemokine receptor class, but not present in other 7TM receptors, and propose a simplified general chemokine receptor pharmacophore of potential utility for future ligand design where this residue acts as a central anchor point. Representative antagonists for CCR1, CCR2, CCR3 and CCR5 are discussed in light of this hypothesis and related to results from site-directed mutagenesis. In the second article, Purandare and Somerville present the validation of the chemokine receptor CCR4 as target in inflammatory and autoimmune diseases, and the current status of small-molecule CCR4 antagonists. Busch-Petersen concludes the chemokine section by reviewing the currently known classes of antagonists for the interleukin 8 receptors CXCR2 and CXCR1, and the effort to develop these ligands into new antiinflammatory drugs. Only a tenth the size of the chemokines, bradykinin and related small peptides act as pro-inflammatory autacoids through the receptors B1 and B2. Fortin and Marceau review the kallikrein-kinin system, the validation of the two kinin receptors as anti-inflammatory targets, the current status on development of selective peptide and non-peptide modulators of these receptors, and the outlook for developing new drugs from these. Scaling down the size of the messenger molecule by another order of magnitude, histamine is a well-known mediator of allergic and inflammatory responses.........