Some effects of putative G-protein biased mu-opioid receptor agonists in male rhesus monkeys

Abstract

G-protein-biased mu-opioid receptor (GPB-MOR) agonists are an emerging class of compounds being evaluated as candidate analgesics and agonist medications for opioid use disorder. Most of the basic pharmacology of GPB-MOR agonists has been conducted in rodents and much less is known how the basic behavioral pharmacology of these compounds translates to nonhuman primates. The present study determined the antinociceptive potency and time course of three putative GPB-MOR agonists: (+)-oliceridine (i.e. TRV130), SR14968, and SR17018 in male rhesus monkeys (n\u2009=\u20093). In addition, the respiratory effects of these compounds were also indirectly determined using a pulse oximeter to measure percent peripheral oxygen saturation (%SpO2). The largest intramuscular oliceridine dose (3.2\u2009mg/kg) produced significant antinociception at 50°C, but not 54°C, and peak effects were between 10 and 30\u2009min. Oliceridine also decreased SpO2 below the 90% threshold that would be clinically categorized as hypoxia in two out of three monkeys. The largest intramuscular SR14968 dose (0.32\u2009mg/kg) produced 100% MPE at 50°C, but not 54°C, in two out of three monkeys, and peak effects were between 30 and 100\u2009min. The largest intravenous SR17018 dose (1\u2009mg/kg) produced 100% MPE at 50°C, but not 54°C, in the same two out of three monkeys, and peak effects were between 30 and 100\u2009min. Solubility limitations for both SR14968 and SR17018 impaired our ability to determine in-vivo potency and effectiveness on antinociceptive and %SpO2 measures for these two compounds.