Pharmacological characterization of the bifunctional opioid ligand H-Dmt-Tic-Gly-NH-Bzl (UFP-505)

Background While producing good-quality analgesia, µ-opioid (MOP) receptor activation produces a number of side-effects including tolerance. Simultaneous blockade of ä-opioid (DOP) receptors has been shown to reduce tolerance to morphine. Here, we characterize a prototype bifunctional opioid H-Dmt-Tic-Gly-NH-Bzl (UFP-505). Methods We measured receptor binding affinity in Chinese hamster ovary (CHO) cells expressing recombinant human MOP, DOP, k-opioid (KOP), nociceptin/orphanin (NOP) receptors. For activation, we measured the binding of GTPã35S to membranes from CHOhMOP, CHOhDOP, rat cerebrocortex, and rat spinal cord. In addition, we assessed ‘end organ’ responses in the guinea pig ileum and mouse vas deferens. Results UFP-505 bound to CHOhMOP and CHOhDOP with (binding affinity) pKi values of 7.79 and 9.82, respectively. There was a weak interaction at KOP and NOP (pKi 6.29 and 5.86). At CHOhMOP, UFP-505 stimulated GTPã35S binding with potency (pEC50) of 6.37 and in CHOhDOP reversed the effects of a DOP agonist with affinity (pKb) of 9.81 (in agreement with pKi at DOP). UFP-505 also stimulated GTPã35S binding in rat cerebrocortex and spinal cord with pEC50 values of 6.11–6.53. In the guinea pig ileum (MOP-rich preparation), UFP-505 inhibited contractility with pEC50 of 7.50 and in the vas deferens (DOP-rich preparation) reversed the effects of a DOP agonist with an affinity (pA2) of 9.15. Conclusions We have shown in a range of preparations and assays that UFP-505 behaves as a potent MOP agonist and DOP antagonist; a MOP/DOP bifunctional opioid. Further studies in dual expression systems and whole animals with this prototype are warranted.