(+)-Catharanthine potentiates the GABAA receptor by binding to a transmembrane site at the β(+)/α(-) interface near the TM2-TM3 loop

Arias, Hugo R.; Borghese, Cecilia M.; Germann, Allison L.; Pierce, Spencer R.; Bonardi, Alessandro; Nocentini, Alessio; Gratteri, Paola; Thodati, Thanvi M.; Lim, Natalie J; Harris, R. Adron

doi:10.1016/j.bcp.2022.114993

Biochemical Pharmacology

2022

DOI: 10.1016/j.bcp.2022.114993

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(+)-Catharanthine potentiates the GABAA receptor by binding to a transmembrane site at the β(+)/α(-) interface near the TM2-TM3 loop

Hugo R. Arias

Cecilia M. Borghese

Allison L. Germann

et al.

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Cited by 3 publications

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“…Normalized PMR (A) and cumulative motor activity (B) are reduced as the potentiating effect of a drug increases. Multiples of control peak response express the electrophysiological potentiating effects of 0.03− 10 μM KK-235, 0.01−3 μM ACN, 1−10 μM propofol, and 0.25−50 μM etomidate on the control response to GABA (P A = 0.035).The multiples of control peak responses to propofol and etomidate were calculated within the framework of the cyclic coagonist model19 and the activation parameters for propofol and etomidate reported previously 9,22.…”

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confidence: 99%

Comparison of Behavioral Effects of GABAergic Low- and High-Efficacy Neuroactive Steroids in the Zebrafish Larvae Assay

Germann,

Xu,

Covey

et al. 2024

ACS Chem. Neurosci.

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Activation of the GABA A receptor is associated with numerous behavioral end points ranging from anxiolysis to deep anesthesia. The specific behavioral effect of a GABAergic compound is considered to correlate with the degree of its functional effect on the receptor. Here, we tested the hypothesis that a low-efficacy allosteric potentiator of the GABA A receptor may act, due to a ceiling effect, as a sedative with reduced and limited action. We synthesized a derivative, named (3α,5β)-20methyl-pregnane-3,20-diol (KK-235), of the GABAergic neurosteroid 5β-pregnane-3α,20α-diol. Using electrophysiology, we showed that KK-235 is a low-efficacy potentiator of the synaptictype α1β2γ2L GABA A receptor. In the zebrafish larvae behavioral assay, KK-235 was found to only partially block the inverted photomotor response (PMR) and to weakly reduce swimming behavior, whereas the high-efficacy GABAergic steroid (3α,5α,17β)-3-hydroxyandrostane-17-carbonitrile (ACN) fully blocked PMR and spontaneous swimming. Coapplication of KK-235 reduced the potentiating effect of ACN in an electrophysiological assay and dampened its sedative effect in behavioral experiments. We propose that low-efficacy GABAergic potentiators may be useful as sedatives with limited action.

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Comparison of Behavioral Effects of GABAergic Low- and High-Efficacy Neuroactive Steroids in the Zebrafish Larvae Assay

Germann,

Xu,

Covey

et al. 2024

ACS Chem. Neurosci.

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Coronaridine congeners induce sedative and anxiolytic-like activity in naïve and stressed/anxious mice by allosteric mechanisms involving increased GABAA receptor affinity for GABA

Arias

Deurwaerdère

Scholze

et al. 2023

European Journal of Pharmacology

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Coronaridine congeners induce anticonvulsant activity in rodents by hippocampal mechanisms involving mainly potentiation of GABAA receptors

Arias,

Kazmierska-Grebowska,

Kowalczyk

et al. 2024

European Journal of Pharmacology

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(+)-Catharanthine potentiates the GABAA receptor by binding to a transmembrane site at the β(+)/α(-) interface near the TM2-TM3 loop

Cited by 3 publications

References 44 publications

Comparison of Behavioral Effects of GABAergic Low- and High-Efficacy Neuroactive Steroids in the Zebrafish Larvae Assay

Comparison of Behavioral Effects of GABAergic Low- and High-Efficacy Neuroactive Steroids in the Zebrafish Larvae Assay

Coronaridine congeners induce sedative and anxiolytic-like activity in naïve and stressed/anxious mice by allosteric mechanisms involving increased GABAA receptor affinity for GABA

Coronaridine congeners induce anticonvulsant activity in rodents by hippocampal mechanisms involving mainly potentiation of GABAA receptors

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