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

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

  • Eur J Med Chem. 2014 Mar 21;75:426-37. doi: 10.1016/j.ejmech.2014.01.035.
Subhrangsu Roy 1,  Roddy J Large 1,  Adebola Morayo Akande 2,  Aravind Kshatri 2,  Tim I Webb 1,  Carmen Domene 3,  Gerard P Sergeant 4,  Noel G McHale 4,  Keith D Thornbury 4,  Mark A Hollywood 5
Affiliations

Affiliations

  • 1 Ion Channel Biotechnology Centre, Dundalk Institute of Technology, Dublin Road, Dundalk, County Louth, Ireland.
  • 2 The Smooth Muscle Research Centre, Dundalk Institute of Technology, Dublin Road, Dundalk, County Louth, Ireland.
  • 3 Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK; Department of Chemistry, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
  • 4 The Smooth Muscle Research Centre, Dundalk Institute of Technology, Dublin Road, Dundalk, County Louth, Ireland; Ion Channel Biotechnology Centre, Dundalk Institute of Technology, Dublin Road, Dundalk, County Louth, Ireland.
  • 5 The Smooth Muscle Research Centre, Dundalk Institute of Technology, Dublin Road, Dundalk, County Louth, Ireland; Ion Channel Biotechnology Centre, Dundalk Institute of Technology, Dublin Road, Dundalk, County Louth, Ireland. Electronic address: mark.hollywood@dkit.ie.
PMID: 24561672 DOI: 10.1016/j.ejmech.2014.01.035
Abstract

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.

Keywords

Anthraquinone derivatives; BK channel activator; Bladder; Ion channels; Ullmann coupling reaction.

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