Neuropeptide FF and Its Receptors: Therapeutic Applications and Ligand Development.

The endogenous neuropeptide FF (NPFF) and its two cognate G protein-coupled receptors, Neuropeptide FF Receptors 1 and 2 (NPFFR1 and NPFFR2), represent a relatively new target system for many therapeutic applications including pain regulation, modulation of opioid side effects, drug reward, anxiety, cardiovascular conditions, and other peripheral effects. Since the cloning of NPFFR1 and NPFFR2 in 2000, significant progress has been made to understand their pharmacological roles and interactions with other receptor systems, notably the opioid receptors. A variety of NPFFR ligands with different mechanisms of action (agonists or antagonists) have been discovered although with limited subtype selectivities. Differential pharmacological effects have been observed for many of these NPFFR ligands, depending on assays/models employed and routes of administration. In this Perspective, we highlight the therapeutic potentials, current knowledge gaps, and latest updates of the development of peptidic and small molecule NPFFR ligands as tool compounds and therapeutic candidates.