NPFFR1 (neuropeptide FF receptor 1) is a G-protein-coupled receptor that primarily binds neuropeptide FF (NPFF) and RFamide-related peptide 3 (RFRP-3), mediating diverse physiological functions through Gαi/o signaling pathways that inhibit cAMP production 1. The receptor exhibits distinct ligand selectivity patterns, with structural studies revealing that the C-terminal RF-amide motif binds conserved transmembrane residues while N-terminal peptide regions determine receptor subtype specificity 2. NPFFR1 plays critical roles in cardiovascular regulation, with renal expression contributing to blood pressure control through antagonistic interactions with dopamine D1-like receptors in renal proximal tubule cells 3. The receptor is also involved in neuroendocrine regulation, particularly prolactin secretion, where RFRP-3 binding to NPFFR1 stimulates prolactin release independently of tuberoinfundibular dopaminergic neuron inhibition 4. NPFFR1 has therapeutic potential for treating pain, opioid tolerance, metabolic disorders, and hypertension 5. The receptor represents an evolutionarily conserved system within the RFamide peptide family, with structural similarities to invertebrate SIFamide receptors suggesting ancient origins 6. Understanding NPFFR1's selective ligand recognition mechanisms provides opportunities for developing targeted therapeutics with enhanced specificity.