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

• A series of novel anthraquinone derivatives were synthesized.
• Their effects were examined on BK channels from bladder smooth muscle membranes.
• Activation V1/2 was shifted up to −100 mV by these BK channel agonists.
• Potency increased 10-fold when naphthylamine was coupled to the anthraquinone core.
• These compounds are amongst the most potent BK channel openers synthesized to date.

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.

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