Carbamazepine derivatives with P2X4 receptor-blocking activity

被引：36

作者：

Tian, Maoqun ^{[1
]}

Abdelrahman, Aliaa ^{[1
]}

Weinhausen, Stephanie ^{[1
]}

Hinz, Sonja ^{[1
]}

Weyer, Stefanie ^{[1
]}

Dosa, Stefan ^{[1
]}

El-Tayeb, Ali ^{[1
]}

Mueller, Christa E. ^{[1
]}

机构：

[1] Univ Bonn, Inst Pharmaceut, PharmaCtr Bonn, D-53121 Bonn, Germany

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2014年 / 22卷 / 03期

关键词：

Heterocycles; Inflammation; Ligand-gated ion channel; Negative allosteric modulator; Neuropathic pain; P2X4; receptor; Structure-activity relationship; Synthesis; Tricyclics; NEUROPATHIC PAIN; ION-CHANNEL; MICROGLIA; ACTIVATION; INDOLES; 5H-DIBENZ<B; F>AZEPINE; INVOLVEMENT; MECHANISMS; ACRIDINES; LIGANDS;

D O I：

10.1016/j.bmc.2013.12.035

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Antagonists for the P2 receptor subtype P2X4, an ATP-activated cation channel receptor, have potential as novel drugs for the treatment of neuropathic pain and other inflammatory diseases. In the present study, a series of 47 carbamazepine derivatives including 32 novel compounds were designed, synthesized, and evaluated as P2X4 receptor antagonists. Their potency to inhibit ATP-induced calcium influx in 1321N1 astrocytoma cells stably transfected with the human P2X4 receptor was determined. Additionally, species selectivity (human, rat, mouse) and receptor subtype selectivity (P2X4 vs P2X1, 2, 3, 7) were investigated for selected derivatives. The most potent compound of the present series, which exhibited an allosteric mechanism of P2X4 inhibition, was N,N-diisopropyl-5H-dibenz[b,f] azepine-5-carboxamide (34, IC50 of 3.44 mu M). The present study extends the so far very limited knowledge on structure-activity relationships of P2X4 receptor antagonists. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：1077 / 1088

页数：12

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