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

TY - JOUR

T1 - Development of GoSlo-SR-5-69, a potent activator of large conductance Ca2+-activated K+ (BK) channels

AU - Roy, Subhrangsu

AU - Large, Roddy J.

AU - Akande, Adebola Morayo

AU - Kshatri, Aravind

AU - Webb, Tim I.

AU - Domene, Carmen

AU - Sergeant, Gerard P.

AU - McHale, Noel G.

AU - Thornbury, Keith D.

AU - Hollywood, Mark A.

PY - 2014/3/21

Y1 - 2014/3/21

N2 - 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. (C) 2014 Elsevier Masson SAS. All rights reserved.

AB - 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. (C) 2014 Elsevier Masson SAS. All rights reserved.

KW - Ion channels

KW - Anthraquinone derivatives

KW - Ullmann coupling reaction

KW - BK channel activator

KW - Bladder

KW - SMOOTH-MUSCLE-CELLS

KW - PIG URINARY-BLADDER

KW - POTASSIUM CHANNELS

KW - CAENORHABDITIS-ELEGANS

KW - SPONTANEOUS EXCITATION

KW - TRANSMITTER RELEASE

KW - OVERACTIVE BLADDER

KW - DERIVATIVES

KW - REPOLARIZATION

KW - MODULATORS

U2 - 10.1016/j.ejmech.2014.01.035

DO - 10.1016/j.ejmech.2014.01.035

M3 - Article

SN - 0223-5234

VL - 75

SP - 426

EP - 437

JO - EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

JF - EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

ER -