Voltage-gated potassium channels are significantly involved in cell function. They participate in establishing resting membrane potential and in determination of the duration of the action potential. They are also involved in cellular processes as proliferation, activation, cell volume regulation, and cell apoptosis. Voltage-gated potassium channels KV1.3 are broadly expressed in many cells in human body, where they are significantly involved in physiological and pathophysiological processes. Cells that play important roles in cancer, autoimmune and chronic inflammatory diseases, may have increased expression of KV1.3 channel. Potassium channels KV1.3 could be important markers for these diseases and new targets for the treatment of these diseases. Potassium channel KV1.3 inhibitors offer potential to reduce the division of cancer cells, to promote their apoptosis, and to prevent tumor to spread.
In this master degree we synthesized five potential inhibitors of voltage-gated potassium channels KV1.3. Compound I (IC50 = 920 nM), which is the published inhibitor of this channel, was selected as the lead compound. We designed and synthesized other similar compounds based on the structure of compound I and tested whether they successfully inhibited the channel function. We determined which structural parts of the new compounds were important for inhibitory activity on KV1.3 channels. One of the five potential inhibitors, compound 3, which incorporated tetrahydropyran ring in the structure, showed 87% inhibitory activity on the KV1.3 channel, therefore we determined its IC50 value for KV1.3 (IC50 = 4.3 μM). Tetrahydropyran and benzene ring, substituted with methyl group at meta site, in compound 3 are probably the most important structural parts that are important for successful inhibition of the KV1.3 channel. Other synthesized compounds did not successfully inhibit the KV1.3 channel.
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