Current Topics in Medicinal Chemistry - Volume 20, Issue 31, 2020

Opioid agonists elicit their analgesic action mainly via μ opioid receptors; however, their use is limited because of adverse events including constipation and respiratory depression. It has been shown that analgesic action is transduced by the G protein-mediated pathway whereas adverse events are by the β-arrestin-mediated pathway through μ opioid receptor signaling. The first new-generation opioid TRV130, which preferentially activates G protein- but not β-arrestin-mediated signal, was constructed and developed to reduce adverse events. TRV130 and other G protein-biased compounds tend to elicit desirable analgesic action with less adverse effects. In clinical trials, the intravenous TRV130 (oliceridine) was evaluated in Phase I, II and III clinical studies. Here we review the discovery and synthesis of TRV130, its main action as a novel analgesic having less adverse events, its up-to-date status in clinical trials, and additional concerns about TRV130 as demonstrated in the literature.

Opioids are widely used for pain management in moderate-to-severe pain. However, opioids are associated with adverse events, such as constipation and emesis/vomiting. To reduce these undesired effects, a structure–activity relationship study of morphinan derivatives was conducted, and a promising lead compound with inhibitory effects on opioid receptors was obtained. Further improvement in the potency and pharmacokinetic profiles of the lead compound led to the discovery of naldemedine, which showed anti-constipation and anti-emetic effects against these adverse events that were induced by morphine without influencing morphine’s analgesic effect. Naldemedine was launched in Japan and the USA in 2017 and in the EU in 2019, for treating opioid-induced constipation.

Background and Objective: The recent alarming reports related to “opioid crisis” necessitate the development of safer and effective analgesics without unwanted side effects. Thus, there needs to be an alternative target or strategy for the development of drugs for the treatment of opioid use/abuse. As one of the novel targets, in these two decades, ligands targeting opioid receptor “heteromerization” including mu-opioid receptor (MOPr)-delta opioid receptor (DOPr) heteromer have been proposed and the pharmacological advancement of reduced side effects has been broadly accepted and well recognized. In this review, some of the ligands targeting both MOPr and DOPr or MOPr-DOPr heteromers are introduced especially focusing on their pharmacological effects in vivo. Conclusion: It has been found that most of those ligands possess potent antinociceptive activity (as much as or higher than that of morphine) with reduced side effects such as tolerance. In addition, some of them are also able to reduce or prevent physiological withdrawal symptoms observed under chronic opioid use. Importantly, there are an increasing number of evidence that show changes in heteromer expression in various pathological animal models and these strongly argue for targeting heteromers for the development of the next generation of pain medication in the near future.

Opioid signaling plays a central role in pain perception. As such, it remains the main target in the development of antinociceptive agents, despite serious side effects involved. In recent years, hopes for improved opioid painkillers are rising, together with our understanding of allosterism and biased signaling mechanisms. In this review, we focus on recently discovered allosteric modulators of opioid receptors, insights into phenomena underlying their action, as well as on how they extend our understanding of mechanisms of previously known compounds. A brief overlook of their synthesis is also presented.

Since a μ-opioid receptor gene containing multiple exons has been identified, the variety of splice variants for μ-opioid receptors have been reported in various species. Amidino-TAPA and IBNtxA have been discovered as new analgesics with different pharmacological profiles from morphine. These new analgesics show a very potent analgesic effect but do not have dependence liability. Interestingly, these analgesics show the selectivity to the morphine-insensitive μ-opioid receptor splice variants. The splice variants, sensitive to these new analgesics but insensitive to morphine, may be a better molecular target to develop the analgesics without side effects.

Despite similar distribution patterns and intracellular events observed in the nociceptin/ orphanin FQ peptide (NOP) receptor and other opioid receptors, NOP receptor activation displays unique pharmacological profiles. Several researchers have identified a variety of peptide and nonpeptide ligands to determine the functional roles of NOP receptor activation and observed that NOP receptor- related ligands exhibit pain modality-dependent pain processing. Importantly, NOP receptor activation results in anti-nociception and anti-hypersensitivity at the spinal and supraspinal levels regardless of the experimental settings in non-human primates (NHPs). Given that the NOP receptor agonists synergistically enhance mu-opioid peptide (MOP) receptor agonist-induced anti-nociception, it has been hypothesized that dual NOP and MOP receptor agonists may display promising functional properties as analgesics. Accumulating evidence indicates that the mixed NOP/opioid receptor agonists demonstrate favorable functional profiles. In NHP studies, bifunctional NOP/MOP partial agonists (e.g., AT-121, BU08028, and BU10038) exerted potent anti-nociception via NOP and MOP receptor activation; however, dose-limiting adverse effects associated with the MOP receptor activation, including respiratory depression, itch sensation, physical dependence, and abuse liability, were not observed. Moreover, a mixed NOP/opioid receptor agonist, cebranopadol, presented promising outcomes in clinical trials as a novel analgesic. Collectively, the dual agonistic actions on NOP and MOP receptors, with appropriate binding affinities and efficacies, may be a viable strategy to develop innovative and safe analgesics.

The discovery of δ opioid receptor inverse agonist activity induced by ICI-174,864, which was previously reported as an δ opioid receptor antagonist, opened the door for the investigation of inverse agonism/constitutive activity of the receptors. Various peptidic or non-peptidic δ opioid receptor inverse agonists have since been developed. Compared with the reports dealing with in vitro inverse agonist activities of novel compounds or known compounds as antagonists, there have been almost no publications describing the in vivo pharmacological effects induced by a δ opioid receptor inverse agonist. After the observation of anorectic effects with the δ opioid receptor antagonism was discussed in the early 2000s, the short-term memory improving effects and antitussive effects have been very recently reported as possible pharmacological effects induced by a δ opioid receptor inverse agonist. In this review, we will survey the developed δ opioid receptor inverse agonists and summarize the possible in vivo pharmacological effects by δ opioid receptor inverse agonists. Moreover, we will discuss important issues involved in the investigation of the in vivo pharmacological effects produced by a δ opioid receptor inverse agonist.