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

作者：Roy Subhrangsu; Large Roddy J; Akande Adebola Morayo; Kshatri Aravind; Webb Tim I; Domene Carmen; Sergeant Gerard P; McHale Noel G; Thornbury Keith D; Hollywood Mark A^*

来源：European Journal of Medicinal Chemistry, 2014, 75: 426-437.

DOI：10.1016/j.ejmech.2014.01.035

• Ion channels
• Anthraquinone derivatives
• Ullmann coupling reaction
• BK channel activator
• Bladder

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 (V-1/2) 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 V-1/2, by -24+/-6 mV and -54+/-8 mV, respectively, whereas the cycloheptane and cyclooctane derivatives shifted the V-1/2 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 V-1/2 by greater than 100 mV when applied at a concentration of 1 mu M and had an EC50 of 251 nM, making it one of the most potent and efficacious BK channel openers synthesised to date.

• 出版日期2014-3-21