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Synthesis of mixed MOR/KOR efficacy cyclic opioid peptide analogs with antinociceptive activity after systemic administration

Perlikowska, Renata and Piekielna, Justyna and Gentilucci, Luca and De Marco, Rossella and Cerlesi, Maria Camilla and Tömböly, Csaba (2016) Synthesis of mixed MOR/KOR efficacy cyclic opioid peptide analogs with antinociceptive activity after systemic administration. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 109. pp. 276-286. ISSN 0223-5234

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Abstract

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- versus position 4-modified analogs. © 2015 Published by Elsevier Masson SAS.

Item Type: Article
Uncontrolled Keywords: systemic therapy; structure activity relation; receptor binding; proton nuclear magnetic resonance; nonhuman; MOUSE; Male; hot plate test; drug synthesis; drug efficacy; dose response; controlled study; calcium mobilization; ARTICLE; animal model; animal experiment; unclassified drug; phenylalanine; opiate peptide; mu opiate receptor; kappa opiate receptor; endomorphin 2; cyclopeptide; cyclic opioid peptide derivative; antinociceptive agent; ROESY; Molecular docking; HOT-PLATE TEST; endomorphins; conformational analysis; Calcium mobilization assay; binding studies; ANTINOCICEPTION
Subjects: Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3011 Biochemistry / biokémia
Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3015 Molecular biology / molekuláris biológia
SWORD Depositor: MTMT SWORD
Depositing User: MTMT SWORD
Date Deposited: 01 Mar 2017 12:13
Last Modified: 01 Mar 2017 12:13
URI: http://real.mtak.hu/id/eprint/49903

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