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 peptidomimetic compounds, i.e. Tyr-NH-C(Me)(2)-CH(2)-O-Phe-NH(2 )(1), Tyr-NH-C(6)H(5)-(o)-CH(2)-CH(2)-O-Phe-NH(2) (2), Tyr-NH-CH(2)-CH(2)-O-Phe-NH(2) (3) and Tyr-NH-CH(D-Et)-CH(2)-O-Phe-NH(2) (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-alpha (TNF-alpha) 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 mu-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 beta-funaltrexamine hydrochloride (mu-opioid receptor antagonist). The immunosuppressive effect of compound 3 was further demonstrated by inhibition of TNF-alpha and nitric oxide production in lipopolysaccharide-stimulated human PBMCs and mouse macrophage cells RAW 264.7, respectively.


CONCLUSIONS
These observations suggest that compound 3 inhibits MLR through mu-opioid receptor present on cells.
Narayan
P
P
Department of Immunology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow, India.
Singh
V K
VK
Agarwal
S S
SS
Tandon
R
R
Haq
W
W
Raghubir
R
R
Dhar
M M
MM
D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D015213:Neuroimmunomodulation / Q000187:drug effects* / Q000502:physiology; D009569:Nitric Oxide / Q000276:immunology / Q000378:metabolism*; D018847:Opioid Peptides / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
D009292:Narcotic Antagonists; D018847:Opioid Peptides; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D009270:Naloxone; D009271:Naltrexone; C024524:beta-funaltrexamine