Pharmacology/Drug Development

Pain management is a challenging and unmet medical need. Despite their demonstrated efficacy, currently used opioid drugs and nonsteroidal anti-inflammatory drugs are frequently associated with several adverse events. The identification of new and safe analgesics is therefore needed. MP1104, an analogue of 3'-iodobenzoyl naltrexamine, is a potent nonselective full agonist at mu (MOR), kappa (KOR), and delta (DOR) opioid receptors, respectively. It was shown to possess potent antinociceptive effects in acute thermal pain assays without aversion in mice. In this study, we investigated MP1104 in the formalin test, a model of tonic pain. MP1104 (0.05, 0.1, and 1.0 mg/kg) reduced pain-like behaviors in phases I and II of the formalin test in male and female ICR mice. Pretreatment with KOR antagonist (norbinaltorphimine 10 mg/kg) and DOR antagonist (naltrindole 10 mg/kg) abolished the antinociceptive effects of MP1104 in the formalin test. These findings support the development of MP1104 for further testing in other pain models.

There is unmet need to design an analgesic with fewer side effects for severe pain management. Although traditional opioids are the most effective painkillers, they are accompanied by severe adverse responses, such as respiratory depression, constipation symptoms, tolerance, withdrawal, and addiction. We indicated BPR1M97 as a dual mu opioid receptor (MOP)/nociceptin-orphanin FQ peptide (NOP) receptor full agonist and investigated the pharmacology of BPR1M97 in multiple animal models. In vitro studies on BPR1M97 were assessed using cyclic-adenosine monophosphate production, β-arrestin, internalization, and membrane potential assays. In vivo studies were characterized using the tail-flick, tail-clip, lung functional, heart functional, acetone drop, von Frey hair, charcoal meal, glass bead, locomotor activity, conditioned place preference (CPP) and naloxone precipitation tests. BPR1M97 elicited full agonist properties for all cell-based assays tested in MOP-expressing cells. However, it acted as a G protein-biased agonist for NOP. BPR1M97 initiated faster antinociceptive effects at 10 min after subcutaneous injection and elicited better analgesia in cancer-induced pain than morphine. Unlike morphine, BPR1M97 caused less respiratory, cardiovascular, and gastrointestinal dysfunction. In addition, BPR1M97 decreased global activity and induced less withdrawal jumping precipitated by naloxone. Thus, BPR1M97 could serve as a novel small molecule dual receptor agonist for antinociception with fewer side effects than morphine.

The present study characterized the behavioral pharmacology of a novel, mixed-action delta-selective (78:1) opioid receptor agonist, BBI-11008. This glycopeptide drug candidate was tested in assays assessing antinociception (acute, inflammatory, and neuropathic pain-like conditions) and side-effect endpoints (respiratory depression and drug self-administration).