Carbamazepine derivatives with P2X4 receptor-blocking activity |
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| Affiliation: | 1. Erasmus University Medical Center Rotterdam, Department of Medical Microbiology & Infectious Diseases, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands;2. National Institute for Public Health and the Environment (RIVM), National Mycobacteria Reference Laboratory, Bilthoven, The Netherlands;3. Radboud University Medical Center, Department of Pharmacy, Nijmegen, The Netherlands;4. Radboud University Nijmegen Medical Center, University Centre for Chronic Diseases Dekkerswald, Nijmegen, The Netherlands;1. Polymer Chemistry and Technology Research Laboratory, Department of Pharmaceutical Chemistry, Indo-Soviet Friendship (I.S.F), College of Pharmacy, Ferozepur Road, Moga 142 001, India;2. Research Scholar, Uttarakhand Technical University, Dehradun 248 007, India;3. The University of Georgia, College of Pharmacy, GA 30602, USA;4. School of Pharmacy, Asmara College of Health Sciences, Asmara, Eritrea;1. Third World Center for Science and Technology (TWC), H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, 75270 Karachi, Pakistan;2. H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, 75270 Karachi, Pakistan;3. Dr. Panjwani Center for Molecular Medicine and Drug Research (PCMD), International Center for Chemical and Biological Sciences, University of Karachi, 75270 Karachi, Pakistan;4. Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21412, Saudi Arabia;5. Department of Chemistry, Faculty of Science and Technology, Universitas Airlangga, Komplek, Campus C, Surabaya 60115, Indonesia;1. Department of Structural and Functional Biology, Institute of Biology, State University of Campinas (UNICAMP), Campinas, SP, Brazil;2. PharmaCenter Bonn, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany |
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| 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 3.44 μM). The present study extends the so far very limited knowledge on structure–activity relationships of P2X4 receptor antagonists. |
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| Keywords: | Heterocycles Inflammation Ligand-gated ion channel Negative allosteric modulator Neuropathic pain P2X4 receptor Structure–activity relationship Synthesis Tricyclics |
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