European journal of medicinal chemistry · 2023
Immunosuppressive effects of new thiophene-based KV1.3 inhibitors.
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Gubič Špela, Montalbano Alberto, Sala Cesare, Becchetti Andrea, Hendrickx Louise Antonia, Van Theemsche Kenny M, Pinheiro-Junior Ernesto Lopes, Altadonna Ginevra Chioccioli, Peigneur Steve, Ilaš Janez, Labro Alain J, Pardo Luis A, Tytgat Jan, Tomašič Tihomir, Arcangeli Annarosa, Peterlin Mašič Lucija
Аннотация
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.