Development of GoSlo-SR-5-69, a potent activator of large conductance Ca2+-activated K+ (BK) channels

Subhrangsu Roy, Roddy J. Large, Adebola Morayo Akande, Aravind Kshatri, Tim I. Webb, Carmen Domene Nunez, Gerard P. Sergeant, Noel G. McHale, Keith D. Thornbury, Mark A. Hollywood

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Abstract

We have designed, synthesised and characterised the effects of a number of novel anthraquinone derivatives and assessed their effects on large conductance, Ca2+ activated K+ (BK) channels recorded from rabbit bladder smooth muscle cells using the excised, inside/out configuration of the patch clamp technique. These compounds are members of the GoSlo-SR family of compounds, which potently open BK channels and shift the voltage required for half maximal activation (V1/2) negatively. The efficacy of the anilinoanthraquinone derivatives was enhanced when the size of ring D was increased, since the cyclopentane and cyclohexane derivatives shifted the V1/2, by −24 ± 6 mV and −54 ± 8 mV, respectively, whereas the cycloheptane and cyclooctane derivatives shifted the V1/2 by −61 ± 6 mV and −106 ± 6 mV. To examine if a combination of hydrophobicity and steric bulking of this region further enhanced their ability to open BK channels, we synthesised a number of naphthalene and tetrahydro-naphthalene derivatives. The tetrahydro-2-naphthalene derivative GoSlo-SR-5-69 was the most potent and efficacious of the series since it was able to shift the activation V1/2 by greater than −100 mV when applied at a concentration of 1 μM and had an EC50 of 251 nM, making it one of the most potent and efficacious BK channel openers synthesised to date.
Original languageEnglish
Pages (from-to)426-437
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume75
DOIs
Publication statusPublished - 21 Mar 2014

Keywords

  • Ion channels, Anthraquinone derivatives, Ullmann coupling reaction, BK channel activator, Bladder, SMOOTH-MUSCLE-CELLS, PIG URINARY-BLADDER, POTASSIUM CHANNELS, CAENORHABDITIS-ELEGANS, SPONTANEOUS EXCITATION, TRANSMITTER RELEASE, OVERACTIVE BLADDER, DERIVATIVES, REPOLARIZATION, MODULATORS

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    Roy, S., Large, R. J., Akande, A. M., Kshatri, A., Webb, T. I., Domene Nunez, C., Sergeant, G. P., McHale, N. G., Thornbury, K. D., & Hollywood, M. A. (2014). Development of GoSlo-SR-5-69, a potent activator of large conductance Ca2+-activated K+ (BK) channels. European Journal of Medicinal Chemistry, 75, 426-437. https://doi.org/10.1016/j.ejmech.2014.01.035