Respiratory depression induced by the novel opioid agonist PZM21

R. Hill¹, A. Disney², A. Conibear¹, K. Sutcliffe¹, S. Husbands², C. Bailey², E. Kelly¹, G. Henderson¹. ¹PPN, University of Bristol, Bristol, United Kingdom, ²Pharmacy, University of Bath, Bath, United Kingdom.

Introduction: PZM21 is a novel opioid agonist reported to activate G-protein signalling but not arrestin signalling through the μ-opioid receptor (MOPr)[1]. PZM21 was also reported to have a decreased side effect profile. In particular PZM21 was reported to be devoid of respiratory depressant effects, a common unwanted side effect of opioid analgesics. We have investigated the signalling and respiratory depressant effects of PZM21 and compared it to morphine, the prototypic opioid.

Methods: Bioluminescence resonance energy transfer (BRET) in HEK 293 cells expressing MOPr was used to investigate the relative activation of Gi-protein signalling and arrestin-3 recruitment by PZM21, morphine and DAMGO at MOPr [2]. Depression of respiration by PZM21 and morphine was measured by whole body plethysmography in male mice (C57BL and CD-1) breathing either 95% air/5% CO₂ or 100% air [3]. Saline was used as the drug vehicle for the in vivo experiments.

Results: PZM21 (0.01-30 μM) induced little recruitment of arrestin-3 to MOPr in the BRET assay but did cause significant Gi activation (EC₅₀ = 0.27 μM). For G-protein activation PZM21 was a partial agonist with higher efficacy than morphine but lower efficacy than DAMGO. N = 3-4 for all groups. Acute administration of morphine (10 mg/kg i.p.) significantly depressed respiration in mice breathing either 100% air or 95% air/5% CO₂ compared to saline controls (n=6 for all groups, p<0.05, Two-way ANOVA). Acute administration of an equi-analgesic dose of PZM21 (40 mg/kg i.p.) produced significant respiratory depression under both breathing conditions that was similar in extent to that observed following injection of morphine (n=6 for all groups, p<0.05, Two-Way ANOVA). The depression of respiration by PZM21 and morphine persisted over the 90 min of the recording period and resulted from a decrease in respiratory rate, not tidal volume. PZM21-induced respiratory depression was completely prevented by prior injection of naloxone (1 mg/kg i.p.).

Conclusions: These data demonstrate that PZM21 is a MOPr agonist that does not recruit arrestin to the receptor but which produces significant, sustained respiratory depression.

References:

1. Manglik et al., 2016 Nature 537:185-190

2. Sutcliffe et al., 2017 J Mol Biol 429(12):1840-1851

3. Hill et al., 2016 Neuropsychopharm 41(3):762-773