Deuterated buprenorphine retains pharmacodynamic properties of buprenorphine

Buprenorphine (BUP) is an opioid that is an effective treatment for opioid use disorder (OUD). However, evidence from our group and others suggests that when it is taken during pregnancy, its active metabolite norbuprenorphine (NorBUP) contributes to neonatal opioid withdrawal syndrome without significantly contributing to treatment. Therefore, reducing or eliminating metabolism of BUP to NorBUP without altering its therapeutic and side effect profile is a novel strategy that will likely lower total fetal exposure to opioids and thus improve offspring outcomes. Precision deuteration is a chemical modification that alters pharmacokinetics without altering pharmacodynamics. Here we report the first synthesis of deuterated buprenorphine (BUP-D2) and initial tests of its pharmacodynamics relative to buprenorphine. Using homogenates made from cells that were transfected with the human mu, delta, or kappa opioid receptors, we measured receptor-binding affinity of BUP-D2 (relative to BUP) using competition receptor binding assays. We also used these homogenates to measure potency and efficacy of BUP-D2 (relative to BUP) to activate G-proteins in the [35S]GTPγS binding assay. Finally, we used the warm-water tail withdrawal assay to compare the antinociceptive effects of BUP-D2 and BUP. Our two-step synthesis method provided a 48% yield and the product was ≥99% deuterated. Like BUP, BUP-D2 had sub-nanomolar affinity for opioid receptors. BUP-D2 also activated opioid receptors and induced antinociception with equal potency and efficacy relative to BUP. These results indicate that BUP-D2 retains key pharmacodynamic properties of BUP and therefore holds promise as an alternative to BUP. GRAPHICAL ABSTRACT