Immunosuppressive effects of new thiophene-based K_V1.3 inhibitors

Voltage-gated potassium channel K_V1.3 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, K_V1.3 inhibition, and immunosuppressive effects of new thiophene-based K_V1.3 inhibitors with nanomolar potency on K⁺ current in T-lymphocytes and K_V1.3 inhibition on Ltk^- cells. The new K_V1.3 inhibitor trans-18 inhibited K_V1.3 -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 K_V1.3 inhibitor trans-18 also had nanomolar potency against K_V1.3 in Xenopus laevis oocytes (IC₅₀ = 136 nM). The novel thiophene-based K_V1.3 inhibitors impaired intracellular Ca²⁺ signaling as well as T-cell activation, proliferation, and colony formation.