Structure-Activity Study on the Phe Side Chain Arrangement of Endomorphins Using Conformationally Constrained Analogues

C. Tömböly, K. Kövér, A. Péter, Dirk Tourwé, Dauren Biyashev, S. Benyhe, A. Borsodi, M. Al-Khrasani, A. Rónai, Géza Tóth

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Abstract

Endomorphins-1 and -2 were substituted with all the β-MePhe stereoisomers in their Phe residues to generate a conformationally constrained peptide set. This series of molecules was subjected to biological assays, and for β-MePhe4 -endomorphins-2, a conformational analysis was performed. Incorporation of (2S,3S)-β-MePhe4 resulted in the most potent analogues of both endomorphins with enhanced enzymatic stability. Their μ opioid affinities were 4-times higher than the parent peptides, they stimulated [35S]GTPγS binding, and they were found to be full agonists. NMR experiments revealed that C-terminal (2S,3S)-β-MePhe in endomorphin-2 strongly favored the gauche (-) spatial orientation which implies the presence of the χ1 = -60° rotamer of Phe4 in the binding conformer of endomorphins. Our results emphasize that the appropriate orientation of the C-terminal aromatic side chain of endomorphins is substantial for binding to the μ opioid receptor.

Original languageEnglish
Pages (from-to)735-743
Number of pages9
JournalJournal of Medicinal Chemistry
Volume47
Issue number3
DOIs
Publication statusPublished - Jan 29 2004

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Peptides
Stereoisomerism
Opioid Receptors
Biological Assay
Opioid Analgesics
Assays
Nuclear magnetic resonance
Molecules
Experiments
endomorphin 2

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

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title = "Structure-Activity Study on the Phe Side Chain Arrangement of Endomorphins Using Conformationally Constrained Analogues",
abstract = "Endomorphins-1 and -2 were substituted with all the β-MePhe stereoisomers in their Phe residues to generate a conformationally constrained peptide set. This series of molecules was subjected to biological assays, and for β-MePhe4 -endomorphins-2, a conformational analysis was performed. Incorporation of (2S,3S)-β-MePhe4 resulted in the most potent analogues of both endomorphins with enhanced enzymatic stability. Their μ opioid affinities were 4-times higher than the parent peptides, they stimulated [35S]GTPγS binding, and they were found to be full agonists. NMR experiments revealed that C-terminal (2S,3S)-β-MePhe in endomorphin-2 strongly favored the gauche (-) spatial orientation which implies the presence of the χ1 = -60° rotamer of Phe4 in the binding conformer of endomorphins. Our results emphasize that the appropriate orientation of the C-terminal aromatic side chain of endomorphins is substantial for binding to the μ opioid receptor.",
author = "C. T{\"o}mb{\"o}ly and K. K{\"o}v{\'e}r and A. P{\'e}ter and Dirk Tourw{\'e} and Dauren Biyashev and S. Benyhe and A. Borsodi and M. Al-Khrasani and A. R{\'o}nai and G{\'e}za T{\'o}th",
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AU - Tömböly, C.

AU - Kövér, K.

AU - Péter, A.

AU - Tourwé, Dirk

AU - Biyashev, Dauren

AU - Benyhe, S.

AU - Borsodi, A.

AU - Al-Khrasani, M.

AU - Rónai, A.

AU - Tóth, Géza

PY - 2004/1/29

Y1 - 2004/1/29

N2 - Endomorphins-1 and -2 were substituted with all the β-MePhe stereoisomers in their Phe residues to generate a conformationally constrained peptide set. This series of molecules was subjected to biological assays, and for β-MePhe4 -endomorphins-2, a conformational analysis was performed. Incorporation of (2S,3S)-β-MePhe4 resulted in the most potent analogues of both endomorphins with enhanced enzymatic stability. Their μ opioid affinities were 4-times higher than the parent peptides, they stimulated [35S]GTPγS binding, and they were found to be full agonists. NMR experiments revealed that C-terminal (2S,3S)-β-MePhe in endomorphin-2 strongly favored the gauche (-) spatial orientation which implies the presence of the χ1 = -60° rotamer of Phe4 in the binding conformer of endomorphins. Our results emphasize that the appropriate orientation of the C-terminal aromatic side chain of endomorphins is substantial for binding to the μ opioid receptor.

AB - Endomorphins-1 and -2 were substituted with all the β-MePhe stereoisomers in their Phe residues to generate a conformationally constrained peptide set. This series of molecules was subjected to biological assays, and for β-MePhe4 -endomorphins-2, a conformational analysis was performed. Incorporation of (2S,3S)-β-MePhe4 resulted in the most potent analogues of both endomorphins with enhanced enzymatic stability. Their μ opioid affinities were 4-times higher than the parent peptides, they stimulated [35S]GTPγS binding, and they were found to be full agonists. NMR experiments revealed that C-terminal (2S,3S)-β-MePhe in endomorphin-2 strongly favored the gauche (-) spatial orientation which implies the presence of the χ1 = -60° rotamer of Phe4 in the binding conformer of endomorphins. Our results emphasize that the appropriate orientation of the C-terminal aromatic side chain of endomorphins is substantial for binding to the μ opioid receptor.

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