Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Chemistry, Medicinal, Pharmacology & Pharmacy, Ion channel, KV1, 3 inhibitor, T-lymphocyte, Immunosuppressive, GATED POTASSIUM CHANNEL, MEMORY T-CELLS, K+ CHANNELS, ION CHANNELS, PAP-1, LYMPHOCYTES, MECHANISM, BLOCKERS, K(V)1.3, DESIGN, K(V)1.3 inhibitor, Animals, Mammals, Potassium Channel Blockers, Potassium Channels, Potassium Channels, Voltage-Gated, Structure-Activity Relationship, T-Lymphocytes, Thiophenes, Immunosuppressive Agents, G0A4919N#54971236, 0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, 3214 Pharmacology and pharmaceutical sciences, 3404 Medicinal and biomolecular chemistry, 3405 Organic chemistry

Abstract:

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.