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χ-Space Screening of Dermorphin-Based Tetrapeptides through Use of Constrained Arylazepinone and Quinolinone Scaffolds.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2017-10-04 , DOI: 10.1021/acsmedchemlett.7b00347 Olivier Van der Poorten 1 , Robin Van Den Hauwe 1 , Emilie Eiselt 2 , Cecilia Betti 1 , Karel Guillemyn 1 , Nga N Chung 3 , François Hallé 4 , Frédéric Bihel 4 , Peter W Schiller 3 , Dirk Tourwé 1 , Philippe Sarret 2 , Louis Gendron 2 , Steven Ballet 1
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2017-10-04 , DOI: 10.1021/acsmedchemlett.7b00347 Olivier Van der Poorten 1 , Robin Van Den Hauwe 1 , Emilie Eiselt 2 , Cecilia Betti 1 , Karel Guillemyn 1 , Nga N Chung 3 , François Hallé 4 , Frédéric Bihel 4 , Peter W Schiller 3 , Dirk Tourwé 1 , Philippe Sarret 2 , Louis Gendron 2 , Steven Ballet 1
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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.
中文翻译：
通过使用约束的Arylazepinone和quinolinone支架在基于Dermorphin的四肽中进行χ-空间筛选。
本文中，合成了新的构象受限的氨基酸，4-氨基-8-溴-2-苯并enza庚因-3-一个（8-Br-Aba），3-氨基-3,4-二氢喹啉-2-一和区域异构体描述了4-氨基萘并pin庚酮（1-和2-Ana）。将这些收缩的支架引入dermorphin的N端四肽（即H-Tyr-d-Ala-Phe-Gly-NH2）会导致结合亲和力，选择性以及在μ-和δ-处的体外活性发生明显变化阿片受体（分别为MOP和DOP）。报道的受约束的μ-/δ-阿片样物质四肽铅H-Dmt-d-Arg-Aba-Gly-NH2通过应用各种受约束的结构单元进行修饰，以鉴于阿片样物质受体的活性确定最佳的空间方向。有趣的是，当芳香族部分转向肽序列的C端时，
更新日期：2017-10-09
中文翻译：
通过使用约束的Arylazepinone和quinolinone支架在基于Dermorphin的四肽中进行χ-空间筛选。
本文中，合成了新的构象受限的氨基酸，4-氨基-8-溴-2-苯并enza庚因-3-一个（8-Br-Aba），3-氨基-3,4-二氢喹啉-2-一和区域异构体描述了4-氨基萘并pin庚酮（1-和2-Ana）。将这些收缩的支架引入dermorphin的N端四肽（即H-Tyr-d-Ala-Phe-Gly-NH2）会导致结合亲和力，选择性以及在μ-和δ-处的体外活性发生明显变化阿片受体（分别为MOP和DOP）。报道的受约束的μ-/δ-阿片样物质四肽铅H-Dmt-d-Arg-Aba-Gly-NH2通过应用各种受约束的结构单元进行修饰，以鉴于阿片样物质受体的活性确定最佳的空间方向。有趣的是，当芳香族部分转向肽序列的C端时，
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