• Journal Article

Discovery of Novel Proline-​Based Neuropeptide FF Receptor Antagonists


Nguyen, T., Decker, A., Langston, T., Mathews, K. M., Siemian, J., Li, J-X., ... Zhang, Y. (2017). Discovery of Novel Proline-​Based Neuropeptide FF Receptor Antagonists. ACS Chemical Neuroscience.


The neuropeptide FF (NPFF) system has been implicated in a no. of physiol. processes including modulating the pharmacol. activity of opioid analgesics and several other classes of drugs of abuse. In this study, we report the discovery of a novel proline scaffold with antagonistic activity at the NPFF receptors through a high throughput screening campaign using a functional calcium mobilization assay. Focused structure-​activity relationship studies on the initial hit 1 have resulted in several analogs with calcium mobilization potencies in the submicromolar range and modest selectivity for the NPFF1 receptor. Affinities and potencies of these compds. were confirmed in radioligand binding and functional cAMP assays. Two compds. 16 and 33 had good soly. and blood-​brain barrier permeability that fall within the range of CNS permeant candidates without the liability of being a P-​glycoprotein substrate. Finally, both compds. reversed fentanyl-​induced hyperalgesia in rats when administered i.p. Together, these results point to the potential of these proline analogs as promising NPFF receptor antagonists.