Bioinformatic analysis of sequence databases to identify new GPCR family members based on homology and conserved 'motifs' to known GPCRs suggests that the total number of GPCRs is likely to be around 350 (this does not include olfactory, taste or opsin receptors, see chapter 1). Of these 350, the number which are currently classified as 'orphans' (that is receptors without a defined physiologically relevant ligand) is in the region of 175. These 'orphans' typically show low sequence identity (<40%) to known receptors and are distributed throughout the entire GPCR phylogenetic tree. A large number show greater sequence identity to each other than to any known GPCR suggesting they are new subfamilies with distinct, possibly novel ligands.

The pharmaceutical industry and academic community continues to invest considerable resources and efforts in the GPCR family, as it is justifiably perceived as a source of chemically attractive therapeutic targets. There is an ever-increasing effort to evaluate orphan receptors and determine their physiological role. Indeed over the past two years there has been a linear growth in the number of publications describing the pairing of orphan GPCRs with their cognate ligand (Fig. 10.1). The substantial growth of sequence data, bioinformatic advances in sequence analysis, and the development ofsophisticated high-throughput screening technologies may explain this increase in success. This chapter will focus on the advances made in 'enabling' technologies for pairing orphan GPCRs with their cognate or surrogate ligands, and methods to determine which receptors will be of likely therapeutic potential.

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