2. Academic Validation
  3. Carbamazepine derivatives with P2X4 receptor-blocking activity

Carbamazepine derivatives with P2X4 receptor-blocking activity

  • Bioorg Med Chem. 2014 Feb 1;22(3):1077-88. doi: 10.1016/j.bmc.2013.12.035.
Maoqun Tian 1,  Aliaa Abdelrahman 1,  Stephanie Weinhausen 1,  Sonja Hinz 1,  Stefanie Weyer 1,  Stefan Dosa 1,  Ali El-Tayeb 1,  Christa E Müller 2
Affiliations

Affiliations

  • 1 PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
  • 2 PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany. Electronic address: christa.mueller@uni-bonn.de.
PMID: 24411477 DOI: 10.1016/j.bmc.2013.12.035
Abstract

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 3.44μM). The present study extends the so far very limited knowledge on structure-activity relationships of P2X4 Receptor antagonists.

Keywords

Heterocycles; Inflammation; Ligand-gated ion channel; Negative allosteric modulator; Neuropathic pain; P2X4 receptor; Structure–activity relationship; Synthesis; Tricyclics.

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