Background: The
melanocortin α-
melanocyte stimulating hormone (α-
MSH), an endogenous
peptide with high affinity for the
melanocortin 1 receptor (MC1r), has demonstrated prevention and reversal of intestinal and ocular
inflammation in animal models. Preclinical studies were performed to determine whether two MC1r receptor agonists, PL-8177 and PL-8331, exhibit actions and efficacy similar to α-
MSH in preventing and reversing intestinal and ocular
inflammation. Methods: Both PL-8177 and PL-8331 were assessed in a Eurofins LeadProfilingScreen selectivity panel including 72 in vitro assays. PL-8177 and PL-8331 were evaluated in an in vitro assay using human whole blood stimulated by
lipopolysaccharide to determine inhibition of
tumor necrosis factor alpha (TNF-α); for comparison,
adrenocorticotropic hormone (
ACTH) and α-
MSH were used as positive controls. PL-8177, dosed at 0.5, 1.5, and 5.0 μg, was assessed in a cannulated rat model of
dinitrobenzene sulfonic acid (
DNBS)-induced bowel
inflammation versus vehicle and oral
sulfasalazine. PL-8177 was also dosed at 0.3 mg/kg/mouse injected intraperitoneally versus untreated controls and α-
MSH treatment in mice with experimental autoimmune
uveitis (EAU). PL-8331 at 3 doses, 3 times daily, was evaluated in a murine model of
scopolamine-induced
dry eye disease (SiccaSystemTM model), versus twice-daily Restasis® and Xiidra®. Results: Both PL-8177 and PL-8331 demonstrated no significant activity at the 1 μm concentration in any of the 72 in vitro assays. PL-8177 and PL-8331 inhibited
lipopolysaccharide-induced TNF-α to a similar degree as
ACTH and α-
MSH. In the
DNBS rat model of bowel
inflammation, PL-8177 was significantly superior to untreated controls at all 3 doses (P < 0.05) in reducing bowel
inflammation parameters, with effects similar to
sulfasalazine. In the murine EAU model, PL-8177 significantly reduced
retinal inflammation scores versus untreated controls (P = 0.0001) over 3-5 weeks, and to a similar degree as α-
MSH. In the murine
scopolamine-induced model of
dry eye disease, PL-8331 reduced corneal
fluorescein staining scores at all doses, significantly (P = 0.02) for the highest dose (1 × 10-5 mg⋅mL-1), and similarly to Restasis®; Xiidra® demonstrated no effect. Conclusion: The MC1r receptor agonists PL-8177 and PL-8331 exhibited actions similar to those of α-
MSH in preventing and reversing intestinal and ocular
inflammation in preclinical disease models.