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Are orphan G-protein coupled receptors (oGPRs) the next frontier in psychiatric drug targets? Several recent papers suggest that this may finally be the case. G-protein coupled receptors are the target of a large proportion of approved and emerging therapeutic compounds, including for psychiatric illnesses.1,2 The oGPRs are receptors for which the endogenous ligand is not known. The first “orphan” receptor human genomic clone, G-21, was discovered in 1987 using lowstringency hybridization with the β2-adrenergic receptor cDNA.3 G-21 and its rat homologue were subsequently identified as the serotonin-1A (5HT1A) receptor, based on ligand binding studies.4,5 The same year, the dopamine-D2 receptor was also identified in this way.6 Subsequently, many other GPR-like genes were cloned using polymerase chain reaction– based approaches, but for many their identity was unknown.7,8 Since endogenous ligands for these receptors remained unidentified they were classified as oGPRs. “Deorphan ization” is the discovery of these endogenous compounds8 and has led to the identification of several new families of receptors. These include GPRs for nonclassical ligands, including lipids,9 ions, trace amines and adhesion molecules.10 Recently, oGPRs have been associated with psychiatric illnesses, including major depression, and with responsiveness to antidepressants.11,12 These emerging findings highlight their potential importance in susceptibility and treatment of mental illness. Targeting oGPRs may provide novel pharmacological agents for improved treatment of mental illnesses.

Orphans to the rescue: orphan G-protein coupled receptors as new antidepressant targets