Biased Agonism at MOP Opioid Receptors

Opioids are the mainstay of pain management. Their use comes with side effects such as respiratory depression, constipation, addiction and tolerance. Opioids interact with opioid receptors; classical μ (MOP), δ (DOP) and κ (KOP) and non-classical N/OFQ receptor or NOP. Classical is naloxone sensitive and the main target for clinical opioid medications. There is considerable interest in designing MOP opioids with reduced side effects. Opioids couple via G-protein and β-Arrestin pathways and there is strong evidence from knockout animals that ligands biased to G-protein and away from β-Arrestin produce analgesia with reduced side effects. This has been questioned. Recently, oliceridine has been approved for use by FDA. We have studied Oliceridine, PZM21, 381G (Putative G-bias) and 433β (Putative β-Arrestin bias) in; (1) radioligand receptor binding. (2) GTPγ[35S] binding (G-protein pathway), (3) β-Arrestin recruitment and (4) MAPK activation (potentially uses both pathways). Oliceridine, PZM21 and both biased peptides bound to MOP receptor and stimulated GTPγ[35S] binding. Importantly, Oliceridine and PZM21 were partial agonists relative to the endogenous opioid Endomorphin-1. This was confirmed by Oliceridine and PZM21 antagonism of the response to Endomorphin-1. All ligands tested activated MAPK (ERK1/2 but not P38). In a range of β-Arrestin assays 433β and Endomorphin-1 were active, Oliceridine, PZM21 and 381G were not. There was some variation between BRET assay in a neuronal background and pathHunter assay in CHO cells. The BRET assay we had available proved unstable so we manufactured a new line by double expression in a CHO background. This consistent cell background allows comparison with G-protein data. Collectively this thesis has used a range of assays to show differential pathway activation by a number of putative biased ligands. Our most important finding is that Oliceridine and PZM21 are partial agonists at G-protein and this can easily explain potential bias.</p

Preclinical Discovery and Development of oliceridine (Olinvyk®) for the Treatment of Post-Operative Pain

IntroductionOpioids acting at the MOP(mu:µ) receptor produce analgesia but also side-effects. There is debate suggesting opioid receptors produce analgesia via G-protein and side-effects via β-arrestin-2 pathways. Opioids targeting G-proteins over the arrestins (bias) offer potential therapeutic advantages. Oliceridine is a putative MOP, G-protein biased agonist.Areas CoveredOliceridine is selective for MOP receptors with greater activity at G-proteins over arrestins. A substantial body of evidence now points to a simpler pharmacological descriptor of partial agonist. Pre-clinical in vivo data indicates a robust antinociceptive response of shorter duration than morphine. Apollo trials (Phase-III RCT-bunionectomy/abdominoplasty) describe good analgesic efficacy that was non-inferior to morphine with good tolerability and side-effect profile. There is evidence for improved respiratory safety profile. Oliceridine is approved by the FDA.Expert OpinionOliceridine will be an important addition to the clinical armamentarium for use for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate. Respiratory advantage and the possibility of reduced abuse potential are possible advantages over the use of traditional opioids. Based on a number of excellent, highly detailed studies, oliceridine should be described as a partial agonist; this ‘label’ does not matter.</div