Trends in Pharmacological Sciences
Orphan G protein-coupled receptors: a neglected opportunity for pioneer drug discovery
Section snippets
Reverse molecular pharmacology
Until recently, research into the identification of GPCRs as targets for drug discovery has been conducted using the traditional approach illustrated in Fig. 2. For this strategy, the starting point is functional activity, which forms the basis of an assay by which a ligand is identified through purification from biological fluids, cell supernatants or tissue extracts. One example of the success of this strategy is the discovery of the potent vasoconstricting peptide endothelin[39]. Once
Screening strategy
Fig. 3 illustrates the generic strategy that we use for our reverse molecular pharmacological approach. In addition to the EST approach, which has yielded the majority of our collection of orphan receptors, we have also used a number of more traditional approaches such as low-stringency screening, using portions of known GPCRs as hybridization probes, as well as PCR-based methods. By these techniques we have succeeded in identifying more than 70 orphan receptors in addition to those already
Concluding remarks and future challenges
Although orphan GPCRs have been around for over ten years, very few companies have, until recently, been willing to risk their resources to explore opportunities among this category of receptors. However, the environment for the pharmaceutical industry has changed due to the confluence of several major technological advances. The conversion of gene sequences encoding GPCRs to drug targets is substantially aided by the development of combinatorial chemistry methods and miniaturized
Acknowledgements
The authors wish to thank Drs Robert Ruffolo, Christine Debouck, Paul England and George Livi for their critical comments, as well as their continued encouragement and support.
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