The concept of specific receptors for drugs and transmitters is a central tenet of pharmacology, but less than a century ago, this idea met with considerable resistance in the scientific community. To mark the 150th anniversary of the birth of John Newport Langley — one of the founders of the receptor concept — Halliwell and colleagues consider its origins and early development in their Perspective. Transferring to the present, in which the sequencing of the human genome has provided the opportunity to identify novel receptors as therapeutic targets, the Review by Chalmers and Behan describes the use of constitutively active G-protein-coupled receptors in drug discovery and functional genomics. The increase in potential drug targets arising from such approaches translates to an increased need for pure small-molecule drug candidates, and the Review by Ley and Baxendale highlights novel methods for the efficient synthesis of small molecules. Two Reviews focus on biological pathways: Oparil and colleagues discuss clinical-trial data on antihypertensive drugs that target the renin–angiotensin–aldosterone system, which have made a major contribution to reductions in the morbidity and mortality of cardiovascular disease, and Stone and Darlington consider the therapeutic potential of the kynurenine pathway. The Reviews section is completed by Nabel's article, which describes how an understanding of the influence of cyclin-dependent kinases and their inhibitors on tissue remodelling is leading to the development of approaches to treat cancer, cardiovascular disease and inflammatory disorders. And in the final Perspective, Miller proposes a model for FDA reform to reduce the spiralling costs and time that are required for drug development.
