Immunomodulation by opioid peptidomimetic compound

Objective: As a follow-up to our earlier studies on immunomodulation with opioid peptides, we synthesized and evaluated immunomodulatory activity of four peptido-mimetic compounds, i.e. Tyr-NH-C(Me)₂-CH₂-O-Phe-NH₂ (1), Tyr-NH-C₆H₅-(o)-CH₂-CH₂-O-Phe-NH ₂ (2), Tyr-NH-CH₂-CH₂-O-Phe-NH₂(3) and Tyr-NH-CH(D-Et)-CH₂-O-Phe-NH₂ (4). Methods: These compounds were synthesized in solution phase and evaluated for their immunomodulatory properties in vitro by mixed lymphocyte reaction (MLR), proliferation of opioid receptor-expressing cells, production of tumor necrosis factor-α (TNF-α) and nitric oxide. Results: This study shows the immunosuppressive potential of synthetic peptidomimetic compound 3. This compound inhibited two-way MLR and suppressed the proliferation of the μ-opioid receptor expressing human embryonic kidney cells HEK 293 in vitro. Inhibition of MLR by compound 3 was reversed by naloxone (opioid receptor antagonist) and β-funaltrexamine hydrochloride (μ-opioid receptor antagonist). The immunosuppressive effect of compound 3 was further demonstrated by inhibition of TNF-α and nitric oxide production in lipopolysaccharide-stimulated human PBMCs and mouse macrophage cells RAW 264.7, respectively. Conclusion: These observations suggest that compound 3 inhibits MLR through μ-opioid receptor present on cells.