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?2-Homo-Amino Acid Scan of µ-Selective Opioid Tetrapeptide TAPP.

ABSTRACT: TAPP (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 ?2-Homo-amino acid (?2hAA) scan of the TAPP sequence. To this aim, 10 novel analogues have been synthesized and evaluated for µ-opioid and ?-opioid receptor affinity as well as for stability in human plasma. The derivatives included compounds in which a (R)- or (S)-?2-Homo-Homologue replaced the amino acids in the TAPP sequence. The derivatives with (R)- or (S)-?2hPhe4 turned out to bind µOR with affinities equal to that of the parent. ?2hAAs in position 1 and 3 resulted in rather large affinity decreases, but the change differed depending on the stereochemistry. ?2-Homologation in the second position gave derivatives with very poor µOR binding. According to molecular modelling, the presented ?/?-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.

SUBMITTER: Tymecka D

PROVIDER: S-EPMC7288052 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Tymecka Dagmara D Lipiński Piotr F J PFJ Kosson Piotr P Misicka Aleksandra A

Molecules (Basel, Switzerland) 20200525 10

TAPP (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)-β<su ...[more]

PMID: 32466333

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Project description:Background and purposeMorphine activates the µ-opioid receptor without causing its rapid endocytosis. In contrast, full agonists such as [d-Ala(2) -MePhe(4) -Gly-ol]enkephalin (DAMGO) or etonitazene stimulate a rapid and profound internalization. However, the detailed molecular events underlying the differential regulation of receptor trafficking by distinct opioid agonists remain incompletely understood.Experimental approachHere, we have generated phosphosite-specific antibodies for the carboxyl-terminal residues serine 363 (Ser363), threonine 370 (Thr370) and serine 375 (Ser375), which enabled us to selectively detect either the Ser363-, Thr370- or Ser375-phosphorylated form of the receptor.Key resultsWe showed that agonist-induced phosphorylation occurs at Thr370 and Ser375, whereas Ser363 is constitutively phosphorylated in the absence of agonist. We further demonstated that DAMGO and etonitazene stimulated the phosphorylation of both Thr370 and Ser375. In contrast, morphine promoted the phosphorylation of Ser375, but failed to stimulate Thr370 phosphorylation. In the presence of DAMGO, Ser375 phosphorylation occurred at a faster rate than phosphorylation of Thr370, indicating that Ser375 is the primary site of agonist-dependent phosphorylation. Activation of PKC by phorbol 12-myristate 13-acetate increased receptor phosphorylation only on Thr370, but not on Ser375, indicating that Thr370 can also undergo heterologous PKC-mediated phosphorylation. We also showed that µ receptor dephosphorylation can occur within minutes at or near the plasma membrane, and that agonist removal is a major prerequisite for Thr370 and Ser375 dephosphorylation.Conclusions and implicationsTogether, we showed for the first time that distinct agonists stimulate site-specific patterns of phosphorylation, which are intimately related to their ability to elicit µ-opioid receptor sequestration.Linked articleThis article is commented on by Kelly, pp. 294-297 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01387.x.

Dataset Information

?2-Homo-Amino Acid Scan of µ-Selective Opioid Tetrapeptide TAPP.

Publications

β<sup>2</sup>-<i>Homo</i>-Amino Acid Scan of µ-Selective Opioid Tetrapeptide TAPP.

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