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G protein‐coupled receptors (GPCRs) constitute the largest family of receptors and membrane proteins in the human genome with ~800 members of which half are olfactory. GPCRs are activated by a very broad range of endogenous signalling molecules and are involved in a plethora of physiological functions. All GPCRs contain a transmembrane domain, consisting of a bundle of seven α‐helices spanning the cell membrane, and forming the majority of the known ortho‐ or allosteric ligand binding sites. Due to their many physiological functions and the accessible and druggable transmembrane pocket, GPCRs constitute the largest family of drug targets mediating the actions of 34% of currently marketed drugs. GPCRs activate one or more of the four G protein families (G q/11 , G i/o , G s  and G 12/13 ) and/or ß‐arrestin. About a third of the non‐olfactory GPCRs are referred to as orphan receptors which means that their endogenous agonist(s) have not yet been found or firmly established. In this MiniReview, we focus on the orphan GPR139 receptor, for which the aromatic amino acids L‐Trp and L‐Phe as well as ACTH/α‐MSH‐related peptides have been proposed as endogenous agonists. GPR139 has been reported to activate several G protein pathways of which G q/11  is the primary one. The receptor shows the highest expression in the striatum, thalamus, hypothalamus, pituitary and habenula of the human, rat and mouse CNS. We review the surrogate agonists and antagonists that have been published as well as the agonist pharmacophore and binding site. Finally, the putative physiological functions and therapeutic potential are outlined.

Pharmacology and function of the orphan GPR139 G protein‐coupled receptor