The arginine–phenylalanine–amide neuropeptide receptor family: Physiological effects, drug development, and structural insights

The arginine-phenylalanine-amide neuropeptide receptor family comprises a subclass within the G protein-coupled receptor superfamily with crucial roles in physiological regulation. These receptors recognize and bind neuropeptides with an arginine-phenylalanine-amide motif, thereby participating in a variety of biological processes such as energy metabolism, pain perception, and reproductive functions. In this review, we explore the physiological and pathological processes involving these receptors and delve into the structure-activity relationships of their ligand peptides, clarifying the key structural motifs within these neuropeptides that determine their biological activity, pharmacological potency, and receptor selectivity. Particular emphasis is placed on their roles in modulating nociception, regulating appetite, and maintaining reproductive health. Additionally, we discuss the therapeutic potential of structure-based drug design targeting these receptors based on existing cryo-electron microscopy structures. The available structural insights into ligand-binding pockets and G protein-receptor interaction interfaces provide a clear perspective and valuable complement to ligand optimization.