Nonpeptide ligands of neuropeptide FF: current status and structural insights

Neuropeptide FF (NPFF) was first isolated from the bovine brain in 1985 and is linked with a variety of biological activities. NPFF, which belongs to the RF-amide family of Peptides, interacts with two distinct G-protein-coupled receptors, NPFF(1) and NPFF(2). These receptors are distributed throughout the body. The NPFF system was initially described as an anti-opioid system and, while the NPFF system does affect the opioid system, it also has been implicated in pain modulation, changes in arterial blood pressure, feeding behavior and regulation of core body temperature and of monoamine systems. Most of this pharmacology has been realized from the peptide NPFF itself or through peptide analogs. The quest for nonpeptide tools for this receptor system has been limited by low selectivity and poor pharmacokinetic properties. Herein, we summarize the current knowledge from the scientific and patent literature that demonstrates a clear need for future medicinal chemistry efforts.