χ‑Space Screening of Dermorphin-Based Tetrapeptides through Use of Constrained Arylazepinone and Quinolinone Scaffolds

Herein, the synthesis of novel conformationally constrained amino acids, 4-amino-8-bromo-2-benzazepin-3-one (8-Br-Aba), 3-amino-3,4-dihydroquinolin-2-one, and regioisomeric 4-amino-naphthoazepinones (1- and 2-Ana), is described. Introduction of these constricted scaffolds into the N-terminal tetrape...

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Published inACS medicinal chemistry letters Vol. 8; no. 11; pp. 1177 - 1182
Main Authors Van der Poorten, Olivier, Van Den Hauwe, Robin, Eiselt, Emilie, Betti, Cecilia, Guillemyn, Karel, Chung, Nga N, Hallé, François, Bihel, Frédéric, Schiller, Peter W, Tourwé, Dirk, Sarret, Philippe, Gendron, Louis, Ballet, Steven
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 09.11.2017
Amer Chemical Soc
Subjects
Chemical Sciences
Chemistry, Medicinal
Letter
Life Sciences & Biomedicine
Medicinal Chemistry
Pharmacology & Pharmacy
Science & Technology
conformational constraints
3-amino-3,4-dihydroquinolin-2-one
4-amino-2-benzazepin-3-one
4-aminonaphthoazepinones
opioid dermorphin ligands
DESIGN
ANALOGS
SIDE-CHAIN
OPIOID-PEPTIDES
AROMATIC-AMINO-ACIDS
PEPTIDOMIMETICS
BROMINATION
PROTEINS
CYCLIZATION
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Summary:Herein, the synthesis of novel conformationally constrained amino acids, 4-amino-8-bromo-2-benzazepin-3-one (8-Br-Aba), 3-amino-3,4-dihydroquinolin-2-one, and regioisomeric 4-amino-naphthoazepinones (1- and 2-Ana), is described. Introduction of these constricted scaffolds into the N-terminal tetrapeptide of dermorphin (i.e., H-Tyr-d-Ala-Phe-Gly-NH2) induced significant shifts in binding affinity, selectivity, and in vitro activity at the μ- and δ-opioid receptors (MOP and DOP, respectively). A reported constrained μ-/δ-opioid lead tetrapeptide H-Dmt-d-Arg-Aba-Gly-NH2 was modified through application of various constrained building blocks to identify optimal spatial orientations in view of activity at the opioid receptors. Interestingly, when the aromatic moieties were turned toward the C-terminus of the peptide sequences, (partial) (ant)­agonism at MOP and weak (ant)­agonism at DOP were noticed, whereas the incorporation of the 1-Ana residue led toward balanced low nanomolar MOP/DOP binding and in vitro agonism.
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PMCID: PMC5683700
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.7b00347