Mu-Opioid receptor biased ligands: A safer and painless discovery of analgesics?

Abstract

Biased activation of G-protein-coupled receptors (GPCRs) is shifting drug discovery efforts and appears promising for the development of safer drugs. The most effective analgesics to treat acute pain are agonists of the μ opioid receptor (μ-OR), a member of the GPCR superfamily. However, the analgesic use of opioid drugs, such as morphine, is hindered by adverse effects. Only a few μ-OR agonists have been reported to selectively activate the G over β-arrestin signaling pathway, resulting in lower gastrointestinal dysfunction and respiratory suppression. Here, we discuss the strategies that led to the development of biased μ-OR agonists, and potential areas for improvement, with an emphasis on structural aspects of the ligand-receptor recognition process.

The novel μ‐opioid receptor agonist PZM21 depresses respiration and induces tolerance to antinociception

“…PZM21 is therefore very similar to the prototypic opioid morphine, although in vivo it is less potent. While the current dogma is that, for μ receptor agonists, respiratory depression results from activation of arrestin signalling (see Chan et al ., ; Madariaga‐Mazón et al, ; Roth et al, ; Smith et al, ), there is evidence that signalling through G i /G o is also involved in mediating this behaviour. μ Receptor coupling through G i /G o proteins results in activation of G protein‐activated inwardly rectifying potassium channels (GIRKs) and inhibition of voltage‐gated calcium channels (North and Williams, ; Seward et al, ), and it has been reported that the respiratory depression induced by either DAMGO, applied locally in the ventrolateral medulla, or fentanyl, administered systemically, is attenuated in GIRK2 subunit knockout mice (Montandon et al, ).…”

Perioperative opioid analgesia—when is enough too much? A review of opioid-induced tolerance and hyperalgesia

“…The first, herkinorin, activates G proteins with negligible recruitment of β-arrestin 2. It is analgesic with markedly decreased tolerance compared to morphine (91). Herkinorin also exhibits less constipation and respiratory depression (92).…”

“…Two more biased agonists, TRV130 and PZM21 (93) also appear to cause less respiratory depression and constipation than morphine; however, respiratory effects and tolerance were observed for PZM21 in a recent study (Hill et al, BJP 2018). TRV130 causes less tolerance than morphine when administered repeatedly to rodents and was analgesic when administered intravenously to treat acute pain, in a phase 2 clinical studies (91). However, there have been no studies in chronic pain, which would be helpful for identifying beneficial properties relating to tolerance and OIH.…”

Polymorphisms associated with fentanyl pharmacokinetics, pharmacodynamics and adverse effects

“…Due to its high lipophilicity, fentanyl is able to easily cross the blood‐brain barrier (BBB), thus having great potency (between 75 and 200 times more potent than morphine) . Considered as one of the most frequent analgesics, it produces adverse effects such as vomiting, nausea, gastrointestinal constipation, respiratory depression, dependence and tolerance . However, it produces less adverse effects (AEs) than morphine as lower doses are required to obtain similar analgesic effects …”

“…3,5 Considered as one of the most frequent analgesics, 3,4 it produces adverse effects such as vomiting, nausea, gastrointestinal constipation, respiratory depression, dependence and tolerance. 6 However, it produces less adverse effects (AEs) than morphine 7 as lower doses are required to obtain similar analgesic effects. 8 When administered in sublingual doses, fentanyl's calculated bioavailability is 54%.…”