BU08028 Displays a Promising Therapeutic Profile as an Analgesic in Monkeys

BU08028, a novel buprenorphine analog, displays similar receptor binding profile like buprenorphine but with improved binding affinity and efficacy on nociceptin/orphanin FQ peptide (NOP) receptors. The aim of this study was to characterize the pharmacological profile of BU08028 as an analgesic in rhesus monkeys. Systemic administration of BU08028 (0.001-0.01 mg/kg) dose-dependently produced antinociception against acute thermal nociception and capsaicin-induced thermal allodynia. Compared to buprenorphine (0.01-0.1 mg/kg), the antinociceptive effect of BU08028 was more potent and much longer-lasting (i.e., more than 24 hours). BU08028-induced antinociception was attenuated equally by both mu opioid (MOP) receptor antagonist naltrexone (0.03 mg/kg) and NOP antagonist J-113397 (0.1 mg/kg), indicating that BU08028 is a bifunctional MOP/NOP agonist in primates. More importantly, BU08028 at antinociceptive doses did not compromise physiological functions including respiration and cardiovascular activities measured by the radio-telemetric probes. Compared to MOP agonists, buprenorphine and remifentanil, BU08028 did not produce reinforcing effects in monkeys under the progressive-ratio schedule of drug self-administration. These findings demonstrate that BU08028 potently produced long-lasting antinociception in the absence of common side effects associated with MOP agonists in primates. This study strongly supports the therapeutic potential of ligands with mixed MOP/NOP actions as innovative analgesics in humans (Supported by US-PHS grants DA-035359 and DA-032568).