Orphan G protein-coupled receptors and beyond

Since the first discovery of mammalian receptors for adrenaline (beta(2)) and acetylcholine (M-1) in 1986, many G protein-coupled receptors for known ligands have been cloned by protein purification, PCR (polymerase chain reaction) and low stringency hybridization, and they have been identified by expression cloning techniques. Now we are almost out of the known ligands pool. However, through the achievement of the Human Genome Project, numerous orphan receptors (whose natural ligands are not yet found) are also available for analysis. In this review, I would like to review recent achievements in the discovery of natural ligands, to describe useful orphan receptor strategies, and to predict the future of reverse pharmacology.