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 K1 subfamily of voltage-gated potassium channels, K1.1-K1.6, 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 IC values between 1.4 and 6.1 μM against K1.3, K1.4, K1.5 and K1.6 channels. All compounds tested displayed selectivity against K1.1 and K1.2 channels. For confirmation of their activity and selectivity, compounds were additionally evaluated in the second independent system against K1.1-K1.6 and K10.1 channels expressed in Xenopus laevis oocytes under voltage clamp conditions where IC values against K1.3-K1.6 channels for the most active analogues (e.g. 6g) were lower than 1 μM. Because of the observed low sub-micromolar IC 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.