BU08073 a buprenorphine analogue with partial agonist activity at μ-receptors in vitro but long-lasting opioid antagonist activity in vivo in mice

Background and PurposeBuprenorphine is a potent analgesic with high affinity at , and and moderate affinity at nociceptin opioid (NOP) receptors. Nevertheless, NOP receptor activation modulates the in vivo activity of buprenorphine. Structure activity studies were conducted to design buprenorphine analogues with high affinity at each of these receptors and to characterize them in in vitro and in vivo assays. Experimental ApproachCompounds were tested for binding affinity and functional activity using [S-35]GTPS binding at each receptor and a whole-cell fluorescent assay at receptors. BU08073 was evaluated for antinociceptive agonist and antagonist activity and for its effects on anxiety in mice. Key ResultsBU08073 bound with high affinity to all opioid receptors. It had virtually no efficacy at , and NOP receptors, whereas at receptors, BU08073 has similar efficacy as buprenorphine in both functional assays. Alone, BU08073 has anxiogenic activity and produces very little antinociception. However, BU08073 blocks morphine and U50,488-mediated antinociception. This blockade was not evident at 1h post-treatment, but is present at 6h and remains for up to 3-6days. Conclusions and ImplicationsThese studies provide structural requirements for synthesis of universal' opioid ligands. BU08073 had high affinity for all the opioid receptors, with moderate efficacy at receptors and reduced efficacy at NOP receptors, a profile suggesting potential analgesic activity. However, in vivo, BU08073 had long-lasting antagonist activity, indicating that its pharmacokinetics determined both the time course of its effects and what receptor-mediated effects were observed. Linked ArticlesThis article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit