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β(2)-Homo-Amino Acid Scan of µ-Selective Opioid Tetrapeptide TAPP
TAPP (H-Tyr-d-Ala-Phe-Phe-NH(2)) is a potent, µ-selective opioid ligand. In order to gain further insights into pharmacophoric features of this tetrapeptide, we have performed a β(2)-Homo-amino acid (β(2)hAA) scan of the TAPP sequence. To this aim, 10 novel analogues have been synthesized and evalua...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288052/ https://www.ncbi.nlm.nih.gov/pubmed/32466333 http://dx.doi.org/10.3390/molecules25102461 |
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author | Tymecka, Dagmara Lipiński, Piotr F. J. Kosson, Piotr Misicka, Aleksandra |
author_facet | Tymecka, Dagmara Lipiński, Piotr F. J. Kosson, Piotr Misicka, Aleksandra |
author_sort | Tymecka, Dagmara |
collection | PubMed |
description | TAPP (H-Tyr-d-Ala-Phe-Phe-NH(2)) is a potent, µ-selective opioid ligand. In order to gain further insights into pharmacophoric features of this tetrapeptide, we have performed a β(2)-Homo-amino acid (β(2)hAA) 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(2)-Homo-Homologue replaced the amino acids in the TAPP sequence. The derivatives with (R)- or (S)-β(2)hPhe(4) turned out to bind µOR with affinities equal to that of the parent. β(2)hAAs in position 1 and 3 resulted in rather large affinity decreases, but the change differed depending on the stereochemistry. β(2)-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. |
format | Online Article Text |
id | pubmed-7288052 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-72880522020-06-15 β(2)-Homo-Amino Acid Scan of µ-Selective Opioid Tetrapeptide TAPP Tymecka, Dagmara Lipiński, Piotr F. J. Kosson, Piotr Misicka, Aleksandra Molecules Article TAPP (H-Tyr-d-Ala-Phe-Phe-NH(2)) is a potent, µ-selective opioid ligand. In order to gain further insights into pharmacophoric features of this tetrapeptide, we have performed a β(2)-Homo-amino acid (β(2)hAA) 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(2)-Homo-Homologue replaced the amino acids in the TAPP sequence. The derivatives with (R)- or (S)-β(2)hPhe(4) turned out to bind µOR with affinities equal to that of the parent. β(2)hAAs in position 1 and 3 resulted in rather large affinity decreases, but the change differed depending on the stereochemistry. β(2)-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. MDPI 2020-05-25 /pmc/articles/PMC7288052/ /pubmed/32466333 http://dx.doi.org/10.3390/molecules25102461 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Tymecka, Dagmara Lipiński, Piotr F. J. Kosson, Piotr Misicka, Aleksandra β(2)-Homo-Amino Acid Scan of µ-Selective Opioid Tetrapeptide TAPP |
title | β(2)-Homo-Amino Acid Scan of µ-Selective Opioid Tetrapeptide TAPP |
title_full | β(2)-Homo-Amino Acid Scan of µ-Selective Opioid Tetrapeptide TAPP |
title_fullStr | β(2)-Homo-Amino Acid Scan of µ-Selective Opioid Tetrapeptide TAPP |
title_full_unstemmed | β(2)-Homo-Amino Acid Scan of µ-Selective Opioid Tetrapeptide TAPP |
title_short | β(2)-Homo-Amino Acid Scan of µ-Selective Opioid Tetrapeptide TAPP |
title_sort | β(2)-homo-amino acid scan of µ-selective opioid tetrapeptide tapp |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288052/ https://www.ncbi.nlm.nih.gov/pubmed/32466333 http://dx.doi.org/10.3390/molecules25102461 |
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