An orphan receptor is an apparent receptor that has a similar structure to other identified receptors but whose endogenous ligand has not yet been identified. If a ligand for an orphan receptor is later discovered, the receptor is referred to as an "adopted orphan".
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Examples
Examples of orphan receptors are found in the G protein-coupled receptor (GPCR) and nuclear receptor families. GPCR orphan receptors are usually given the name "GPR" followed by a number, for example GPR1.
If an endogenous ligand is found, the orphan receptor is "adopted". An example is the receptor FXR, which is activated by bile acids. Adopted orphan receptors in the nuclear receptor group include the farnesoid X receptor (FXR), liver X receptor (LXR), and peroxisome proliferator-activated receptor (PPAR). Another example of an orphan receptor site is the PCP binding site in the NMDA receptor, a type of ligand-gated ion channel. This is where the recreational drug PCP works, but no endogenous ligand is known for this site.
Discovery
Historically, receptors were discovered by using ligands to "fish" for their receptors. Hence by definition, these receptors were not orphans. However, with modern molecular biology techniques such as screening of cDNA libraries, it becomes possible to identify related receptors based on sequence similarity to known receptors without knowing what their ligands are.