Orphan receptors have been generally defined as proteins with a receptor motif that lack both a ligand and function (88). Approximately 160-300 orphan GPCRs are thought to be in the draft sequence of the human genome and intense efforts are currently ongoing to identify the ligands for these and their function as novel intellectual property for the drug discovery process. Orphan receptor validation can be done using expression profiling to identify tissues rich in the expression of the receptor of interest and a technique known as reverse pharmacology that can be used to identify a ligand for the orphan receptor. In the latter, the orphan receptor is used as "bait" to bind selective ligands. These can then be used to further characterize receptor function (6, 88). Nearly 30 orphan GPCRs have been validated in this manner. While most of the current interest on orphan receptors is focused on GPCRs because of the considerable body of existing knowledge about this receptor class, it is anticipated that orphan receptors will also be discovered for other receptor classes.
The orphan receptor approach to drug discovery is exemplified by the orphanin/FQ receptor, ORL1, a structural homolog of the opioid receptor family (89). Identified in 1995 using a homology-based screening strategy, ORL1 had low affinity for known opioid li-gands. A novel heptadecapeptide ligand for the ORL1 receptor, orphanin/FQ, was subsequently isolated from brain regions rich in ORL1 (90), which provided the key tool to validate the target and identify a functional role for the receptor in stress-related situations in animal models. In turn, after an intensive screening program, an antagonist of this receptor was identified, Ro 64-6198 (91), that represented a novel anxiolytic/antidepressant drug candidate.
Was this article helpful?