Repozytorium
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Inne
Synthesis of mixed MOR/KOR efficacy cyclic opioid peptide analogs with antinociceptive activity after systemic administration.
Autorzy
Rok wydania
2016
Czasopismo
European Journal of Medicinal Chemistry
Numer woluminu
109
Strony
276-286
DOI
10.1016/j.ejmech.2015.12.012
Kolekcja
Język
Angielski
Typ publikacji
Artykuł
Cyclic pentapeptide Tyr-c[D-Lys-Phe-Phe-Asp]NH2, based on the structure of endomorphin-2 (EM-2), which shows high affinity to the μ-opioid receptor (MOR) and a very strong antinociceptive activity in mice was used as a parent compound for the structure–activity relationship studies. In this report we synthesized analogs of a general sequence Dmt-c[D-Lys-Xaa-Yaa-Asp]NH2, with D-1- or D-2-naphthyl-3-alanine (D-1-Nal or D-2-Nal) in positions 3 or 4. In our earlier papers we have indicated that replacing a phenylalanine residue by the more extended aromatic system of naphthylalanines may result in increased bioactivities of linear analogs. The data obtained here showed that only cyclopeptides modified in position 4 retained the sub-nanomolar MOR and nanomolar κ-opioid receptor (KOR) affinity, similar but not better than that of a parent cyclopeptide. In the in vivo mouse hot-plate test, the most potent analog, Dmt-c[D-Lys-Phe-D-1-Nal-Asp]NH2, exhibited higher than EM-2 but slightly lower than the cyclic parent peptide antinociceptive activity after peripheral (ip) and also central administration (icv). Conformational analyses in a biomimetic environment and molecular docking studies disclosed the structural determinants responsible for the different pharmacological profiles of position 3- versusposition 4-modified analogs.
Słowa kluczowe
Endomorphins, Antinociception, binding studies, calcium mobilization assay, Hot-plate test, conformational analysis, ROESY, molecular docking
Adres publiczny
http://dx.doi.org/10.1016/j.ejmech.2015.12.012
Strona internetowa wydawcy
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