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Clathrodin, hymenidin and oroidin, and their synthetic analogues as inhibitors of the voltage-gated potassium channels
Zidar, N.; Zula, A.; Tomašic, T.; Rogers, M.; Kirby, R.W.; Tytgat, J.; Peigneur, S.; Kikelj, D.; Ilas, J.; Masic, L.P. (2017). Clathrodin, hymenidin and oroidin, and their synthetic analogues as inhibitors of the voltage-gated potassium channels. Eur. J. Med. Chem. 139: 232-241. https://hdl.handle.net/10.1016/j.ejmech.2017.08.015
In: European Journal of Medicinal Chemistry. Elsevier: Amsterdam. ISSN 0223-5234; e-ISSN 1768-3254
Peer reviewed article  

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Trefwoord
    Marien
Author keywords
    Voltage-gated potassium channel; K(v)1; Modulator; Inhibitor;Clathrodin; Oroidin; Hymenidin

Auteurs  Top 
  • Zidar, N.
  • Zula, A.
  • Tomašic, T.
  • Rogers, M.
  • Kirby, R.W.
  • Tytgat, J.
  • Peigneur, S.
  • Kikelj, D.
  • Ilas, J.
  • Masic, L.P.

Abstract
    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 Kv1 subfamily of voltage-gated potassium channels, Kv1.1-Kv1.6, expressed in Chinese Hamster ovary (CHO) cells using automated patch clampelectrophysiology 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 Kv1.3, Kv1.4, Kv1.5 and Kv1.6 channels. All compounds tested displayed selectivity against Kv1.1 and Kv1.2 channels. For confirmation of their activity and selectivity, compounds were additionally evaluated in the second independent system against Kv1.1-Kv1.6 and Kv10.1 channels expressed in Xenopus laevis oocytes under voltage clamp conditions where IC50 values against Kv1.3-Kv1.6 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.

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