title: Development of GoSlo-SR-5-69, a potent activator of large conductance Ca2+-activated K+ (BK) channels.
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.
authors.affiliation: Ion Channel Biotechnology Centre, Dundalk Institute of Technology, Dublin Road, Dundalk, County Louth, Ireland.
authors.forename: Subhrangsu
authors.initials: S
authors.lastname: Roy
authors.affiliation: Ion Channel Biotechnology Centre, Dundalk Institute of Technology, Dublin Road, Dundalk, County Louth, Ireland.
authors.forename: Roddy J
authors.initials: RJ
authors.lastname: Large
authors.affiliation: The Smooth Muscle Research Centre, Dundalk Institute of Technology, Dublin Road, Dundalk, County Louth, Ireland.
authors.forename: Adebola Morayo
authors.initials: AM
authors.lastname: Akande
authors.affiliation: The Smooth Muscle Research Centre, Dundalk Institute of Technology, Dublin Road, Dundalk, County Louth, Ireland.
authors.forename: Aravind
authors.initials: A
authors.lastname: Kshatri
authors.affiliation: Ion Channel Biotechnology Centre, Dundalk Institute of Technology, Dublin Road, Dundalk, County Louth, Ireland.
authors.forename: Tim I
authors.initials: TI
authors.lastname: Webb
authors.affiliation: 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.
authors.forename: Carmen
authors.initials: C
authors.lastname: Domene
authors.affiliation: 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.
authors.forename: Gerard P
authors.initials: GP
authors.lastname: Sergeant
authors.affiliation: 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.
authors.forename: Noel G
authors.initials: NG
authors.lastname: McHale
authors.affiliation: 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.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Thornbury
authors.affiliation: 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.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hollywood
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000819:agonists* / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D008958:Models, Molecular; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D011817:Rabbits; D001743:Urinary Bladder / Q000187:drug effects* / Q000502:physiology
chemical_list: D000880:Anthraquinones; D051036:Large-Conductance Calcium-Activated Potassium Channels
keywords: Anthraquinone derivatives; BK channel activator; Bladder; Ion channels; Ullmann coupling reaction