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β2-Homo-Amino Acid Scan of µ-Selective Opioid Tetrapeptide TAPP

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cris.lastimport.scopus2024-02-12T20:36:04Z
dc.abstract.enTAPP (H-Tyr-d-Ala-Phe-Phe-NH2) is a potent, µ-selective opioid ligand. In order to gain further insights into pharmacophoric features of this tetrapeptide, we have performed a β2-Homo-amino acid (β2hAA) scan of the TAPP sequence. To this aim, 10 novel analogues have been synthesized and evaluated for µ-opioid and δ-opioid receptor affinity as well as for stability in human plasma. The derivatives included compounds in which a (R)- or (S)-β2-Homo-Homologue replaced the amino acids in the TAPP sequence. The derivatives with (R)- or (S)-β2hPhe4 turned out to bind µOR with affinities equal to that of the parent. β2hAAs in position 1 and 3 resulted in rather large affinity decreases, but the change differed depending on the stereochemistry. β2-Homologation in the second position gave derivatives with very poor µOR binding. According to molecular modelling, the presented α/β-peptides adopt a variety of binding poses with their common element being an ionic interaction between a protonable amine of the first residue and Asp147. A feature required for high µOR affinity seems the ability to accommodate the ring in the fourth residue in a manner similar to that found for TAPP. Contrary to what might be expected, several compounds were significantly less stable in human plasma than the parent compound.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorMisicka-Kęsik, Aleksandra
dc.contributor.authorLipiński, Piotr
dc.contributor.authorTymecka, Dagmara
dc.contributor.authorKosson, Piotr
dc.date.accessioned2024-01-26T12:28:51Z
dc.date.available2024-01-26T12:28:51Z
dc.date.copyright2020-05-25
dc.date.issued2020
dc.description.accesstimeAT_PUBLICATION
dc.description.financePublikacja bezkosztowa
dc.description.number10
dc.description.versionFINAL_PUBLISHED
dc.description.volume25
dc.identifier.doi10.3390/MOLECULES25102461
dc.identifier.issn1420-3049
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/126166
dc.identifier.weblinkhttps://www.mdpi.com/1420-3049/25/10/2461/pdf
dc.languageeng
dc.pbn.affiliationchemical sciences
dc.relation.ispartofMolecules
dc.relation.pages2461-2479
dc.rightsCC-BY
dc.sciencecloudnosend
dc.subject.enbeta2-amino acids
dc.subject.enbeta2-Homo-amino acids
dc.subject.enu-opioid receptor
dc.subject.enopioid peptides
dc.subject.enTAPP
dc.subject.enracemic synthesis of beta2-amino acids
dc.titleβ2-Homo-Amino Acid Scan of µ-Selective Opioid Tetrapeptide TAPP
dc.typeJournalArticle
dspace.entity.typePublication