The Arg-Phe-amide peptide 26RFa/QRFP and its Receptor. IUPHAR Review.

26RFa is an RFamide neuropeptide that was first isolated from the brain of the European green frog on the basis of a cross-reactivity with antibodies raised against bovine NPFF. 26RFa and its N-terminally extended form QRFP have been identified as cognate ligands of the former orphan receptor GPR103, now renamed QRFPR. The 26RFa/QRFP precursor has been characterized in various mammalian and non-mammalian species. In the brain of mammals, including human, 26RFa/QRFP mRNA is almost exclusively expressed in hypothalamic nuclei. The 26RFa/QRFP transcript is also present in various organs especially in endocrine glands. While human possesses only one QRFPR, two isoforms are present in rodents. The QRFPR genes are widely expressed in the central nervous system and in peripheral tissues notably in bone, heart, kidney, pancreas and testis. Structure-activity relationship studies have led to the identification of low molecular weight peptidergic agonists and antagonists of QRFPR. Concurrently, several selective nonpeptidic antagonists have been designed from high throughput screening hit optimization. Consistent with the widespread distribution of QRFPR mRNA and 26RFa binding sites, 26RFa/QRFP have been shown to exert a large array of biological activities, notably in the control of energy homeostasis, bone formation and nociception, that are mediated by QRFPR or NPFF2. The present report reviews the current knowledge concerning the 26RFa/QRFP-QRFPR system and discusses the potential use of selective QRFPR ligands for future therapeutic applications.