Conformationally restricted κ-opioid receptor agonists: Synthesis and pharmacological evaluation of diastereoisomeric and enantiomeric decahydroquinoxalines

被引：10

作者：

Molenveld, Peter ^{[1
]}

des Mazery, Renaud Bouzanne ^{[1
]}

Sterk, Geert Jan ^{[1
]}

Storcken, Roy P. M. ^{[1
]}

Autar, Reshma ^{[1
]}

van Oss, Bram ^{[1
]}

van der Haas, Richard N. S. ^{[1
]}

Froehlich, Roland ^{[2
]}

Schepmann, Dirk ^{[3
]}

Wuensch, Bernhard ^{[3
]}

Soeberdt, Michael ^{[4
]}

机构：

[1] Mercachem, NL-6546 BB Nijmegen, Netherlands

[2] Univ Munster, Inst Organ Chem, D-48149 Munster, Germany

[3] Univ Munster, Inst Pharmazeut & Med Chem, D-48149 Munster, Germany

[4] Dr August Wolff GmbH & Co KG Arzneimittel, D-33611 Bielefeld, Germany

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 22期

关键词：

kappa agonists; kappa-Opioid receptor; Decahydroquinoxalines; Diastereoisomers; Resolution of enantiomers; Hydrogenation; SAR; Relationship between configuration and kappa affinity; HIGHLY POTENT; STEREOSELECTIVE-SYNTHESIS; DISCOVERY; AFFINITY; RESOLUTION;

D O I：

10.1016/j.bmcl.2015.09.040

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

All diastereoisomeric decahydroquinoxalines representing conformationally restricted analogs of kappa agonists U-50,488 and GR-89,696 have been prepared. Cis/trans configured compound 7 is by far the highest binding diastereoisomer with a K-i of 0.35 nM. Racemates 4, 6, and 7 were separated into enantiomers. (+)-(4aR,5S,8aS)-Configured enantiomer 7b was identified as a high affinity (K-i = 0.25 nM) kappa ligand with high selectivity over mu and delta receptors. It acts as full agonist with an EC50 value of 2.0 nM in the [S-35] GTP gamma S assay, while enantiomer 7a showed an EC50 value of 1000 nM. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：5326 / 5330

页数：5

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