Agonist and antagonist activities on human NPFF2 receptors of the NPY ligands GR231118 and BIBP3226

Neuropeptide FF (NPFF) is a part of a neurotransmitter system acting as a modulator of endogenous opioid functions. At this time, no non-peptide or peptide NPFF-antagonists have been discovered. Here, we demonstrate that Neuropeptide Y (NPY) ligands, in fact possess significant ability to interact with the human NPFF2 receptors. NPY Y1 antagonist BIBP3226 and mixed Y1 antagonist/Y4 agonist GR231118 are able to displace with low aAnity, 50‐100 nM, the specific binding on NPFF receptors expressed in CHO cells as well as in rat dorsal spinal cord, an aAnity however superior to those determined against Y2 ,Y 4 or Y5 receptors. Furthermore, BIBP3226 which is unable to inhibit the forskolin-stimulated cyclic AMP production mediated by NPFF2 receptors, antagonizes the eAect of NPFF, revealing the first antagonist of NPFF receptors. These properties of NPY ligands on Neuropeptide FF receptors must be considered when evaluating pharmacological activities of these drugs. British Journal of Pharmacology (2001) 133, 1‐4