Clathrodin, hymenidin and oroidin, and their synthetic analogues as inhibitors of the voltage-gated potassium channels

We have prepared three alkaloids from the Agelas sponges, clathrodin, hymenidin and oroidin, and a series of their synthetic analogues, and evaluated their inhibitory effect against six isoforms of the K_v1 subfamily of voltage-gated potassium channels, K_v1.1-K_v1.6, expressed in Chinese Hamster ovary (CHO) cells using automated patch clamp electrophysiology assay. The most potent inhibitor was the (E)-N-(3-(2-amino-1H-imidazol-4-yl)allyl)-4,5-dichloro-1H-pyrrole-2-carboxamide (6g) with IC₅₀ values between 1.4 and 6.1 μM against K_v1.3, K_v1.4, K_v1.5 and K_v1.6 channels. All compounds tested displayed selectivity against K_v1.1 and K_v1.2 channels. For confirmation of their activity and selectivity, compounds were additionally evaluated in the second independent system against K_v1.1-K_v1.6 and K_v10.1 channels expressed in Xenopus laevis oocytes under voltage clamp conditions where IC₅₀ values against K_v1.3-K_v1.6 channels for the most active analogues (e.g. 6g) were lower than 1 μM. Because of the observed low sub-micromolar IC₅₀ values and fairly low molecular weights, the prepared compounds represent good starting points for further optimisation towards more potent and selective voltage-gated potassium channel inhibitors.