期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 259, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2023.115561
关键词
Ion channel; KV1; 3 inhibitor; T-lymphocyte; Immunosuppressive
In this study, the structure-activity relationship, KV1.3 inhibition, and immunosuppressive effects of new thiophene-based KV1.3 inhibitors were investigated. The new KV1.3 inhibitor trans-18 showed nanomolar potency in inhibiting KV1.3-mediated current in T-lymphocytes, Ltk- cells, and Xenopus laevis oocytes. Furthermore, these inhibitors impaired intracellular Ca2+ signaling and suppressed T-cell activation, proliferation, and colony formation.
Voltage-gated potassium channel KV1.3 inhibitors have been shown to be effective in preventing T-cell proliferation and activation by affecting intracellular Ca2+ homeostasis. Here, we present the structure-activity relationship, KV1.3 inhibition, and immunosuppressive effects of new thiophene-based KV1.3 inhibitors with nanomolar potency on K+ current in T-lymphocytes and KV1.3 inhibition on Ltk- cells. The new KV1.3 inhibitor trans -18 inhibited KV1.3-mediated current in phytohemagglutinin (PHA)-activated T-lymphocytes with an IC50 value of 26.1 nM and in mammalian Ltk- cells with an IC50 value of 230 nM. The KV1.3 inhibitor trans -18 also had nanomolar potency against KV1.3 in Xenopus laevis oocytes (IC50 = 136 nM). The novel thiophene-based KV1.3 inhibitors impaired intracellular Ca2+ signaling as well as T-cell activation, proliferation, and colony formation.
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