Exploring in vivo metabolism and excretion of QO-58L using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry

Zhang, Jiaqi; Jia, Qingzhong; Qi, Ji; Zhang, Hailin; Wu, Yaru; Shi, Xiaowei

doi:10.1016/j.ejps.2018.02.015

Cited by 1 publication

(2 citation statements)

References 22 publications

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“…Moreover, the sensitivity of voltage-clamped cells (e.g., neuroendocrine or endocrine cells) to QO-58 or other structurally similar compounds (e.g., QO-40) can be expected to depend not only on the QO-58 concentration applied, but also greatly on different confounding variables which include the pre-existing level of resting potential and varying bursting patterns of action potential firing. It is therefore conceivable to reflect that QO-58-mediated concerted stimulation of K M (KCNQx or K V 7x) and BK Ca channels seen in GH 3 cells is of pharmacological or therapeutic relevance, presuming that similar in vivo observations are found [3,8]. ) was supplied by Tocris (Union Biomed, Taipei, Taiwan), iberiotoxin and verruculogen (Ver) were by Alomone (Asia Bioscience, Taipei, Taiwan), while we acquired linopirdine, tetrodotoxin (TTX), and thyrotropin releasing hormone (TRH) from Sigma-Aldrich (Merck, Taipei, Taiwan).…”

Section: Discussionmentioning

confidence: 99%

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Evidence for Dual Activation of IK(M) and IK(Ca) Caused by QO-58 (5-(2,6-Dichloro-5-fluoropyridin-3-yl)-3-phenyl-2-(trifluoromethyl)-1H-pyrazolol[1,5-a]pyrimidin-7-one)

Cho

et al. 2022

IJMS

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QO-58 (5-(2,6-dichloro-5-fluoropyridin-3-yl)-3-phenyl-2-(trifluoromethyl)-1H-pyrazolol[1,5-a]pyrimidin-7-one) has been regarded to be an activator of KV7 channels with analgesic properties. However, whether and how the presence of this compound can result in any modifications of other types of membrane ion channels in native cells are not thoroughly investigated. In this study, we investigated its perturbations on M-type K+ current (IK(M)), Ca2+-activated K+ current (IK(Ca)), large-conductance Ca2+-activated K+ (BKCa) channels, and erg-mediated K+ current (IK(erg)) identified from pituitary tumor (GH3) cells. Addition of QO-58 can increase the amplitude of IK(M) and IK(Ca) in a concentration-dependent fashion, with effective EC50 of 3.1 and 4.2 μM, respectively. This compound could shift the activation curve of IK(M) toward a leftward direction with being void of changes in the gating charge. The strength in voltage-dependent hysteresis (Vhys) of IK(M) evoked by upright triangular ramp pulse (Vramp) was enhanced by adding QO-58. The probabilities of M-type K+ (KM) channels that will be open increased upon the exposure to QO-58, although no modification in single-channel conductance was seen. Furthermore, GH3-cell exposure to QO-58 effectively increased the amplitude of IK(Ca) as well as enhanced the activity of BKCa channels. Under inside-out configuration, QO-58, applied at the cytosolic leaflet of the channel, activated BKCa-channel activity, and its increase could be attenuated by further addition of verruculogen, but not by linopirdine (10 μM). The application of QO-58 could lead to a leftward shift in the activation curve of BKCa channels with neither change in the gating charge nor in single-channel conductance. Moreover, cell exposure of QO-58 (10 μM) resulted in a minor suppression of IK(erg) amplitude in response to membrane hyperpolarization. The docking results also revealed that there are possible interactions of the QO-58 molecule with the KCNQ or KCa1.1 channel. Overall, dual activation of IK(M) and IK(Ca) caused by the presence of QO-58 eventually may have high impacts on the functional activity (e.g., anti-nociceptive effect) residing in electrically excitable cells. Care must be exercised when interpreting data generated with QO-58 as it is not entirely KCNQ/KV7 selective.

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Section: Discussionmentioning

confidence: 99%

“…(K V 7x) channel [1][2][3][4]. It has been reported that this compound could increase the pain threshold of neuropathic pain in a rat model (i.e., chronic constriction injury of the sciatic nerve) [2].…”

mentioning

confidence: 99%

Evidence for Dual Activation of IK(M) and IK(Ca) Caused by QO-58 (5-(2,6-Dichloro-5-fluoropyridin-3-yl)-3-phenyl-2-(trifluoromethyl)-1H-pyrazolol[1,5-a]pyrimidin-7-one)

Cho

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

Exploring in vivo metabolism and excretion of QO-58L using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry

Cited by 1 publication

References 22 publications

Evidence for Dual Activation of IK(M) and IK(Ca) Caused by QO-58 (5-(2,6-Dichloro-5-fluoropyridin-3-yl)-3-phenyl-2-(trifluoromethyl)-1H-pyrazolol[1,5-a]pyrimidin-7-one)

Evidence for Dual Activation of IK(M) and IK(Ca) Caused by QO-58 (5-(2,6-Dichloro-5-fluoropyridin-3-yl)-3-phenyl-2-(trifluoromethyl)-1H-pyrazolol[1,5-a]pyrimidin-7-one)

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