Immunosuppressive effects of new thiophene-based K V 1.3 inhibitors.

Autor: Gubič Š; University of Ljubljana, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia., Montalbano A; University of Florence, Department of Experimental and Clinical Medicine, I-50134, Florence, Italy., Sala C; University of Florence, Department of Experimental and Clinical Medicine, I-50134, Florence, Italy., Becchetti A; University of Milano-Bicocca, Department of Biotechnology and Biosciences, Piazza della Scienza 2, I-20126, Milano, Italy., Hendrickx LA; University of Leuven, Toxicology and Pharmacology, Campus Gasthuisberg, Onderwijs en Navorsing 2, Herestraat 49, PO Box 922, 3000, Leuven, Belgium., Van Theemsche KM; University of Antwerp, Department of Biomedical Sciences, Campus Drie Eiken, Universiteisplein 1, 2610, Wilrijk, Belgium; Ghent University, Department of Basic and Applied Medical Sciences, Corneel Heymanslaan 10, 9000, Ghent, Belgium., Pinheiro-Junior EL; University of Leuven, Toxicology and Pharmacology, Campus Gasthuisberg, Onderwijs en Navorsing 2, Herestraat 49, PO Box 922, 3000, Leuven, Belgium., Altadonna GC; University of Siena, Department of Medical Biotechnologies, I-53100, Siena, Italy., Peigneur S; University of Leuven, Toxicology and Pharmacology, Campus Gasthuisberg, Onderwijs en Navorsing 2, Herestraat 49, PO Box 922, 3000, Leuven, Belgium., Ilaš J; University of Ljubljana, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia., Labro AJ; Ghent University, Department of Basic and Applied Medical Sciences, Corneel Heymanslaan 10, 9000, Ghent, Belgium., Pardo LA; Max-Planck Institute for Experimental Medicine, AG Oncophysiology, Hermann-Rein-Str. 3, 37075, Göttingen, Germany., Tytgat J; University of Leuven, Toxicology and Pharmacology, Campus Gasthuisberg, Onderwijs en Navorsing 2, Herestraat 49, PO Box 922, 3000, Leuven, Belgium., Tomašič T; University of Ljubljana, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia., Arcangeli A; University of Florence, Department of Experimental and Clinical Medicine, I-50134, Florence, Italy. Electronic address: annarosa.arcangeli@unifi.it., Peterlin Mašič L; University of Ljubljana, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia. Electronic address: lucija.peterlinmasic@ffa.uni-lj.si.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2023 Nov 05; Vol. 259, pp. 115561. Date of Electronic Publication: 2023 Jun 25.
DOI: 10.1016/j.ejmech.2023.115561
Abstrakt: Voltage-gated potassium channel K V 1.3 inhibitors have been shown to be effective in preventing T-cell proliferation and activation by affecting intracellular Ca 2+ homeostasis. Here, we present the structure-activity relationship, K V 1.3 inhibition, and immunosuppressive effects of new thiophene-based K V 1.3 inhibitors with nanomolar potency on K + current in T-lymphocytes and K V 1.3 inhibition on Ltk - cells. The new K V 1.3 inhibitor trans-18 inhibited K V 1.3 -mediated current in phytohemagglutinin (PHA)-activated T-lymphocytes with an IC 50 value of 26.1 nM and in mammalian Ltk - cells with an IC 50 value of 230 nM. The K V 1.3 inhibitor trans-18 also had nanomolar potency against K V 1.3 in Xenopus laevis oocytes (IC 50  = 136 nM). The novel thiophene-based K V 1.3 inhibitors impaired intracellular Ca 2+ signaling as well as T-cell activation, proliferation, and colony formation.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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