In vitro and in vivo characterisation of the bifunctional MOP/DOP ligand UFP-505.

Background and purpose: Targeting more than one opioid receptor type simultaneously may have analgesic advantages in reduced side effect profile. We have evaluated the mixed MOP (μ, mu) agonist/DOP (δ, delta) antagonist UFP‐505 in vitro and in vivo. Experimental approach: We measured receptor density and function in single MOP, DOP and MOP/DOP double expression systems. GTPγ35S binding, cAMP formation and arrestin recruitment were measured. Antinociceptive activity was measured in vivo using tail withdrawal and paw pressure tests following acute and chronic treatment. In some experiments we have harvested tissue to measure receptor. Key Results: UFP‐505 bound to MOP and DOP; at MOP this binding resulted in full agonist activity and at DOP there was low efficacy partial agonism. At MOP but not DOP UFP‐505 treatment led to arrestin recruitment. Unlike morphine, UFP‐505 treatment internalized MOP and there was evidence for DOP internalization. Similar data were obtained in a MOP/DOP double expression system. In rats, acute UFP‐505 or morphine treatment was antinociceptive following i.t. administration. In tissues harvested from these experiments there was a reduction in MOP and DOP receptor density for UFP‐505 but not morphine (in agreement with in vitro data). Both Morphine and UFP‐505 induced significant tolerance. Conclusions and Implications:In this study we have shown that UFP‐505 behaves as a full agonist at the MOP receptor with variable activity at DOP. This bifunctional compound produces antinociception in rats via i.t. administration. In this paradigm dual targeting provides no advantages in terms of tolerance liability.