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

Journal article

We have designed, synthesised and characterised the effects of a number of novel anthraquinone derivatives and assessed their effects on large conductance, Ca(2+) 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.

Authors: Roy, S; Large, R; Akande, A; Kshatri, A; Webb, T

• Publication status: Published
• Journal: European journal of medicinal chemistry
• Volume: 75
• Pages: 426-437
• Publication date: 2014-03-01
• DOI: 10.1016/j.ejmech.2014.01.035
• EISSN: 1768-3254
• ISSN: 0223-5234
• Language: English
• Keywords: Rabbits; Models, Molecular; Animals; Muscle, Smooth; Patch-Clamp Techniques; Large-Conductance Calcium-Activated Potassium Channels; Anthraquinones; Urinary Bladder; Membrane Potentials