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Substituted 4-phenyl-2-aminoimidazoles and 4-phenyl-4,5-dihydro-2-aminoimidazoles as voltage-gated sodium channel modulators
Zidar, N.; Jakopin, Z.; Madge, D.; Chan, F.; Tytgat, J.; Peigneur, S.; Dolenc, M.; Tomasic, T.; Ilas, J.; Masic, L.; Kikelj, D. (2014). Substituted 4-phenyl-2-aminoimidazoles and 4-phenyl-4,5-dihydro-2-aminoimidazoles as voltage-gated sodium channel modulators. Eur. J. Med. Chem. 74: 23-30. dx.doi.org/10.1016/j.ejmech.2013.12.034
In: European Journal of Medicinal Chemistry. Elsevier: Amsterdam. ISSN 0223-5234, more
Peer reviewed article  

Available in  Authors 
    VLIZ: Open Repository 292287 [ OMA ]

Keyword
    Marine
Author keywords
    Voltage-gated sodium channel; Na-v channel modulator; Marine alkaloid;Clathrodin; Pyrrole-2-aminoimidazole; 4-Phenyl-2-aminoimidazole

Authors  Top 
  • Zidar, N.
  • Jakopin, Z.
  • Madge, D.
  • Chan, F.
  • Tytgat, J., more
  • Peigneur, S., more
  • Dolenc, M.
  • Tomasic, T.
  • Ilas, J.
  • Masic, L.
  • Kikelj, D.

Abstract
    Voltage-gated sodium channels play an integral part in neurotransmission and their dysfunction is frequently a cause of various neurological disorders. On the basis of the structure of marine alkaloid clathrodin, twenty eight new analogs were designed, synthesized and tested for their ability to block human Na(v)1.3, Na(v)1.4 and Na(v)1.7 channels, as well as for their selectivity against human cardiac isoform Na(v)1.5, using automated patch clamp electrophysiological assay. Several compounds exhibited promising activities on different Na-v channel isoforms in the medium micromolar range and some of the compounds showed also moderate isoform selectivities. The most promising results were obtained for the Na(v)1.3 channel, for which four compounds were found to possess IC50 values lower than 15 mu M. All of the active compounds bind to the open-inactivated states of the channels and therefore act as state-dependent modulators. The obtained results validate the approach of using natural products driven chemistry for drug discovery starting points and represent a good foundation for future design of selective Na-v modulators.

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