Structure-Based Discovery of a NPFF1R Antagonist with Analgesic Activity

Abstract

AbstractWhile opioid drugs remain among the most effective analgesics for pain management, adverse effects limit their use. Molecules that synergize with opioids, increasing analgesia without increasing side effects, could prove beneficial. A potential way to do so is via the RF-amide receptor system, as NPFFR1 agonists reduce µ- opioid receptor (µOR)-based analgesia while antagonists increase it. These inferences are, however, clouded by the lack of selectivity of most NPFF1R ligands. Seeking selective antagonists of the NPFF1R, we screened a large virtual library against a homology model of NPFF1R. From 26 high-ranking molecules that were synthesized and tested, one antagonized NPFF1R with a Kiof 319 nM. Structure-based optimization led to a 22 nM antagonist of NPFF1R, compound56, with selectivity against a large panel of GPCRs. When administered alone,56has no activity in mouse tail-flick nociception assays. However, coadministration of compound 56 and morphine produced significantly greater antinociception than did morphine alone, consistent with the notion that NPFF1R nociceptive activity occurs via modulation of µOR signaling. Surprisingly, in the hot-plate assays56was analgesic by itself, suggesting that NPFF1R alone can also confer analgesia. At equi-analgesic doses, combinations of56with morphine reduced the common constipation side effect of morphine versus using morphine alone. The high selectivity of56and its activity in cooperation with morphine supports further analgesic development against NPFF1R and against the RF-amide family of receptors more generally.