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.
- 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
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