A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates

Abstract

Despite the critical need, no previous research has substantiated safe opioid analgesics without abuse liability in primates. Recent advances in medicinal chemistry have led to the development of ligands with mixed mu opioid peptide (MOP)/nociceptin-orphanin FQ peptide (NOP) receptor agonist activity to achieve this objective. BU08028 is a novel orvinol analog that displays a similar binding profile to buprenorphine with improved affinity and efficacy at NOP receptors. The aim of this preclinical study was to establish the functional profile of BU08028 in monkeys using clinically used MOP receptor agonists for side-by-side comparisons in various wellhoned behavioral and physiological assays. Systemic BU08028 (0.001-0.01 mg/kg) produced potent long-lasting (i.e., >24 h) antinociceptive and antiallodynic effects, which were blocked by MOP or NOP receptor antagonists. More importantly, the reinforcing strength of BU08028 was significantly lower than that of cocaine, remifentanil, or buprenorphine in monkeys responding under a progressive-ratio schedule of drug self-administration. Unlike MOP receptor agonists, BU08028 at antinociceptive doses and ∼10-to 30-fold higher doses did not cause respiratory depression or cardiovascular adverse events as measured by telemetry devices. After repeated administration, the monkeys developed acute physical dependence on morphine, as manifested by precipitated withdrawal signs, such as increased respiratory rate, heart rate, and blood pressure. In contrast, monkeys did not show physical dependence on BU08028. These in vivo findings in primates not only document the efficacy and tolerability profile of bifunctional MOP/NOP receptor agonists, but also provide a means of translating such ligands into therapies as safe and potentially abusefree opioid analgesics.N/OFQ peptide receptor | respiratory depression | reinforcing effects | physical dependence | mu opioid peptide receptor P ain, a symptom of numerous clinical disorders, afflicts millions of people worldwide. Despite the remarkable advances in the identification of potential targets as analgesics in the last decade, mu opioid peptide (MOP) receptor agonists remain the most widely used analgesics for pain management (1). Several side effects associated with MOP receptor agonists have severely limited the value of opioid analgesics, however (2). Owing to the abuse liability and the high mortality rate caused by respiratory arrest, opioid abuse not only has dire consequences, but also leads to mounting medical and economic burdens in our society (3-5). There is a clear, unmet need for safe analgesics without abuse liability in the global community.Buprenorphine, a partial MOP receptor agonist, is considered a safe analgesic because of its ceiling effect on respiratory depression (6, 7). Buprenorphine is commonly used in both human and veterinary medicine to treat various pain conditions, including cancer pain and neuropathic pain (7,8). However, buprenorphine is not devoid of reinforcing effects, the most devastating side effect...

Breaking barriers to novel analgesic drug development

“…NNTA is currently being investigated by Blue Therapeutics via IND-enabling studies for safety with future plans for human clinical trials upon successful filing of the IND package. In addition, bifunctional ligands such as the newly described Buprenorphine small molecule analog, BU08028, for mu and nociceptin opioid receptors, is another potential drug candidate which has displayed potent antinociception devoid of respiratory depression or physical dependence in monkeys 66 .…”

Altered expression of glial markers, chemokines, and opioid receptors in the spinal cord of type 2 diabetic monkeys

“…Spinal NOP receptor agonists exhibit functional plasticity, especially with enhanced analgesic efficacy in rodents under chronic pain such as nerve injury and diabetic neuropathy [61, 62]. Given that the expression of NOP receptors is not affected by diabetes and NOP-related ligands have a wider therapeutic window than MOP agonists in primates [63, 64], it is worth investigating the therapeutic potential of NOP-related ligands as analgesics in diabetic individuals.…”

Designing Safer Analgesics via μ-Opioid Receptor Pathways

“…It shares the most common chemical scaffold of the morphine class of compounds, and is believed to interact with opioid receptors similarly to the ligand observed in the crystal structure [36]. Because BU08028 competes for μOR and NOP with radiolabeled endogenous ligands in binding assays, it is fair to postulate that BU08028 also binds to the orthosteric sites of these two receptors.…”

“…BU08028 produces long-lasting anti-nociceptive effects in both models [36]. However, contributions of μOR and NOP receptors to the anti-nociceptive effects may differ.…”