Wydział Chemii

Karol Wtorek

Piotr F. J. Lipiński

Anna Adamska-Bartłomiejczyk

Justyna Piekielna-Ciesielska

Jarosław Sukiennik

Alicja Kluczyk

Anna Janecka

2022

Molecules

27

151/1-151/14

10.3390/molecules27010151

Naukowa

Angielski

Artykuł

Our formerly described pentapeptide opioid analog Tyr-c[D-Lys-Phe-Phe-Asp]NH2 (designated RP-170), showing high affinity for the mu (MOR) and kappa (KOR) opioid receptors, was muchmore stable than endomorphine-2 (EM-2) in the rat brain homogenate and displayed remarkableantinociceptive activity after central (intracerebroventricular) and peripheral (intravenous) administration.In this report, we describe the further modification of this analog, which includes the incorporation of a 3-amino acid, (R)- and (S)-3-Lys, instead of D-Lys in position 2. The influence of such replacement on the biological properties of the obtained analogs, Tyr-c[(R)-3-Lys-Phe-Phe-Asp]NH2 (RP-171) and Tyr-c[(S)-3-Lys-Phe-Phe-Asp]NH2, (RP-172), was investigated in vitro. Receptor radiolabeled displacement and functional calcium mobilization assays were performed to measure binding affinity and receptor activation of the new analogs. The obtained data revealed that only one of the diastereoisomeric peptides, RP-171, was able to selectively bind and activate MOR. Molecular modeling (docking and molecular dynamics (MD) simulations) suggests that both compounds should be accommodated in the MOR binding site. However, in the case of the inactive isomer RP-172, fewer hydrogen bonds, as well as instability of the canonical ionic interaction to Asp147, could explain its very low MOR affinity.

opioid receptors, -amino acids, peptide synthesis, receptor binding studies, functional assay.

CC-BY

http://dx.doi.org/10.3390/MOLECULES27010151

http://www.mdpi.com/journal/metals