title: Carbamazepine derivatives with P2X4 receptor-blocking activity.
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.
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Maoqun
authors.initials: M
authors.lastname: Tian
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Aliaa
authors.initials: A
authors.lastname: Abdelrahman
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Weinhausen
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Hinz
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Weyer
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Dosa
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Ali
authors.initials: A
authors.lastname: El-Tayeb
authors.affiliation: 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.
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002220:Carbamazepine / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology; D060326:Chemistry Techniques, Synthetic; D003984:Dibenzazepines / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D058920:Purinergic P2X Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D058848:Receptors, Purinergic P2X4 / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D003984:Dibenzazepines; C000592630:N,N-diisopropyl-5H-dibenz(b,f)azepine-5-carboxamide; D058920:Purinergic P2X Receptor Antagonists; D058848:Receptors, Purinergic P2X4; D002220:Carbamazepine; D000255:Adenosine Triphosphate; C527817:dibenzazepine; D002118:Calcium
keywords: Heterocycles; Inflammation; Ligand-gated ion channel; Negative allosteric modulator; Neuropathic pain; P2X4 receptor; Structure–activity relationship; Synthesis; Tricyclics