An orally available mu-opioid receptor biased ligand is analgesic with reduced constipation in rodents

Morphine elicits increased analgesia and decreased constipation and respiratory depression in beta-arrestin2 knockout mice compared to wild-type mice. These effects are all mediated by the mu-opioid receptor, which couples to both G proteins and beta-arrestins, suggesting that drugs selectively engaging G protein coupling may offer increased opioid analgesia with improved safety and tolerability. Trevena has previously described TRV130, a G protein-biased mu-opioid receptor ligand in clinical testing for post-operative analgesia. In preclinical testing, TRV130 showed reduced gastrointestinal dysfunction and respiratory depression compared to equianalgesic doses of morphine. We have subsequently identified TRV734, a molecule with in vitro and in vivo pharmacology highly similar to TRV130. TRV734 robustly engages G protein coupling with efficacy comparable to morphine, oxycodone, and oxymorphone, but displays dramatically reduced beta-arrestin coupling. By both subcutaneous and oral routes, TRV734 is strongly analgesic in rodents, but displays marked improvement in constipation and respiratory depression when compared to subcutaneous morphine or oral oxycodone. Preclinical pharmacokinetics suggest that TRV734 may have good oral availability in humans. The improved therapeutic index of TRV734 could allow safer, more effective pain management than currently used opioids. Supported by Trevena Inc., King of Prussia, PA.