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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...

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Autores principales: Tymecka, Dagmara, Lipiński, Piotr F. J., Kosson, Piotr, Misicka, Aleksandra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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.
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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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