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

Roy, Shibayan; Large, Roddy J.; Akande, Adebola Morayo; Kshatri, Aravind; Webb, Tim; Domene, Carmen; Sergeant, Gerard P.; McHale, Noel G.; Thornbury, Keith D.; Hollywood, Mark A.

doi:10.1016/j.ejmech.2014.01.035

Cited by 24 publications

(38 citation statements)

References 33 publications

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“…4D), as recently suggested (41). This may also help to explain the observation that increasing D ring diameter enhances the efficacy of GoSlo compounds (32), perhaps as a result of forcing S4S5 L and S6C apart.…”

Section: Discussionmentioning

confidence: 52%

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Molecular mechanisms underlying the effect of the novel BK channel opener GoSlo: Involvement of the S4/S5 linker and the S6 segment

Webb

Kshatri

Large

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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GoSlo-SR-5-6 is a novel large-conductance Ca 2+ -activated K + (BK) channel agonist that shifts the activation V 1/2 of these channels in excess of −100 mV when applied at a concentration of 10 μM. Although the structure-activity relationship of this family of molecules has been established, little is known about how they open BK channels. To help address this, we used a combination of electrophysiology, mutagenesis, and mathematical modeling to investigate the molecular mechanisms underlying the effect of GoSlo-SR-5-6. Our data demonstrate that the effects of this agonist are practically abolished when three point mutations are made: L227A in the S4/S5 linker in combination with S317R and I326A in the S6C region. Our data suggest that GoSlo-SR-5-6 interacts with the transmembrane domain of the channel to enhance pore opening. The Horrigan-Aldrich model suggests that GoSlo-SR-5-6 works by stabilizing the open conformation of the channel and the activated state of the voltage sensors, yet decouples the voltage sensors from the pore gate.

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Section: Discussionmentioning

confidence: 52%

“…GoSlo-SR-5-6 (GoSlo) (10 μM) shifted the voltage dependence of activation in excess of −100 mV. Although the structure-activity relationships of these compounds has been established (31,32), little is known about their mode of action on BK channels, other than GoSlo does not require the β 1 -subunit to mediate its effects (33).…”

Section: +mentioning

confidence: 99%

Molecular mechanisms underlying the effect of the novel BK channel opener GoSlo: Involvement of the S4/S5 linker and the S6 segment

Webb

Kshatri

Large

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The structure of NS19504 is markedly different from that of well known BK activators, such as the benzimidazolidin-2-one NS1619, the quinolinone BMS-223131 [4-(5-chloro-2-hydroxyphenyl)-3-(2-hydroxyethyl)-6-(trifluoromethyl)-3,4-dihydro-1H-quinolin-2-one], the oxindole BMS-204352, the anthraquinone analog BK activators of the GoSlo-SR family (Roy et al, 2012(Roy et al, , 2014, and the bisaryl thiourea NS11021 (Bentzen et al, 2007). NS19504 is characterized by a low mol.…”

Section: Discussionmentioning

confidence: 99%

“…More recent studies have identified the bisarylthiourea NS11021 [5-(2-{3-[3,5-bis(trifluoromethyl) phenyl]thioureido}-5-bromophenyl)-1H-1,2,3,4-tetrazole], the oxindole BMS-204352 [(3S)-3-(5-chloro-2-methoxyphenyl)-3-fluoro-6-(trifluoromethyl)-2-indolinone], the natural modulator dihydrosoyasaponin-1 (for review, see Ghatta et al, 2006;Nardi and Olesen, 2008), the GoSlo-SR family of anthraquinone analogs (Roy et al, 2012(Roy et al, , 2014, as well as the tetrahydroquinoline racemate "X" and its two enantiomers "Y" and "Z" (Ponte et al, 2012). Several of these modulators have shown activity in pharmacological studies in ex vivo organ bath studies using bladder strips (Imai et al, 2001;Tanaka et al, 2003;Malysz et al, 2004; Mora and Suarez-Kurtz, 2005; Ponte et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

NS19504: A Novel BK Channel Activator with Relaxing Effect on Bladder Smooth Muscle Spontaneous Phasic Contractions

Nausch

Rode

Jørgensen

et al. 2014

J Pharmacol Exp Ther

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Large-conductance Ca 21 -activated K 1 channels (BK, K Ca 1.1, MaxiK) are important regulators of urinary bladder function and may be an attractive therapeutic target in bladder disorders. In this study, we established a high-throughput fluorometric imaging plate reader-based screening assay for BK channel activators and identified a small-molecule positive modulator, NS19504 (5-[(4-bromophenyl)methyl]-1,3-thiazol-2-amine), which activated the BK channel with an EC 50 value of 11.0 6 1.4 mM. Hit validation was performed using high-throughput electrophysiology (QPatch), and further characterization was achieved in manual whole-cell and inside-out patch-clamp studies in human embryonic kidney 293 cells expressing hBK channels: NS19504 caused distinct activation from a concentration of 0.3 and 10 mM NS19504 left-shifted the voltage activation curve by 60 mV. Furthermore, whole-cell recording showed that NS19504 activated BK channels in native smooth muscle cells from guinea pig urinary bladder. In guinea pig urinary bladder strips, NS19504 (1 mM) reduced spontaneous phasic contractions, an effect that was significantly inhibited by the specific BK channel blocker iberiotoxin. In contrast, NS19504 (1 mM) only modestly inhibited nerve-evoked contractions and had no effect on contractions induced by a high K 1 concentration consistent with a K 1 channel-mediated action. Collectively, these results show that NS19504 is a positive modulator of BK channels and provide support for the role of BK channels in urinary bladder function. The pharmacologic profile of NS19504 indicates that this compound may have the potential to reduce nonvoiding contractions associated with spontaneous bladder overactivity while having a minimal effect on normal voiding.

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“…Depending on the exact experimental conditions, UBSM single BK channel conductance varies from 214 pS in mice (119), 122-244 pS in guinea pigs (48,63,81), 170 -200 pS in rats (130), 330 pS in rabbits (123,124), and 136 -220 pS in humans (58,89,130). A recent study has provided the first systematic characterization of human single BK channel biophysical properties in excised patches of freshly isolated UBSM cells from donor patients (89).…”

Section: Ubsm Bk Channel Structure and Biophysical Propertiesmentioning

confidence: 97%

Central role of the BK channel in urinary bladder smooth muscle physiology and pathophysiology

Petkov

2014

American Journal of Physiology-Regulatory, Integrative and Comp

133

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The physiological functions of the urinary bladder are to store and periodically expel urine. These tasks are facilitated by the contraction and relaxation of the urinary bladder smooth muscle (UBSM), also known as detrusor smooth muscle, which comprises the bladder wall. The large-conductance voltage- and Ca(2+)-activated K(+) (BK, BKCa, MaxiK, Slo1, or KCa1.1) channel is highly expressed in UBSM and is arguably the most important physiologically relevant K(+) channel that regulates UBSM function. Its significance arises from the fact that the BK channel is the only K(+) channel that is activated by increases in both voltage and intracellular Ca(2+). The BK channels control UBSM excitability and contractility by maintaining the resting membrane potential and shaping the repolarization phase of the spontaneous action potentials that determine UBSM spontaneous rhythmic contractility. In UBSM, these channels have complex regulatory mechanisms involving integrated intracellular Ca(2+) signals, protein kinases, phosphodiesterases, and close functional interactions with muscarinic and β-adrenergic receptors. BK channel dysfunction is implicated in some forms of bladder pathologies, such as detrusor overactivity, and related overactive bladder. This review article summarizes the current state of knowledge of the functional role of UBSM BK channels under normal and pathophysiological conditions and provides new insight toward the BK channels as targets for pharmacological or genetic control of UBSM function. Modulation of UBSM BK channels can occur by directly or indirectly targeting their regulatory mechanisms, which has the potential to provide novel therapeutic approaches for bladder dysfunction, such as overactive bladder and detrusor underactivity.

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

Cited by 24 publications

References 33 publications

Molecular mechanisms underlying the effect of the novel BK channel opener GoSlo: Involvement of the S4/S5 linker and the S6 segment

Molecular mechanisms underlying the effect of the novel BK channel opener GoSlo: Involvement of the S4/S5 linker and the S6 segment

NS19504: A Novel BK Channel Activator with Relaxing Effect on Bladder Smooth Muscle Spontaneous Phasic Contractions

Central role of the BK channel in urinary bladder smooth muscle physiology and pathophysiology

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