Subacute toxicity evaluations of LPM3480392 in rats, a full µ-opioid receptor biased agonist

Opiates produce analgesia via G-protein signaling, and adverse effects, such as respiratory depression decreased bowel motility, by β-arrestin pathway. Oliceridine, a G protein-biased MOR agonist, only presents modest safety advantages compared to other opiates in clinical trials, possibly due its limited bias. Our previous study shown that LPM3480392, full biased is selective for the Gi pathway over β-arrestin-2. In present article, we evaluated subacute toxicity of LPM3480392 rats. The rats were administered with control article or 0.6, 1.2 2.4 mg/kg/day 4 consecutive weeks followed 4-week recovery phase. Intravenous infusion was conducted at tail vein 0.2, 0.4 0.8 dosing volume 10 mL/kg 5 min/rat/dose, three times day an interval approximately h. concomitant toxicokinetics conducted. Two unscheduled died no clear cause. For scheduled necropsy, major effects associated agonist-related pharmacodynamic properties (e.g., increased activity, muscle tone; food consumption body weight gain; chemistry changes related consumption) groups. addition, also induced deep respiration histopathology testis epididymis sporadic individual However, different from opiates, weak/no immunosuppression adrenal gland weight, which may be LPM3480392’ At end phase, all findings recovered some extent completely. study, dose-dependent elevation drug exposure observed, partly explained high dose. summary, has exhibited good characteristics this