The Benzodiazepine Binding Sites of GABAA Receptors

Sigel, Erwin; Ernst, Margot

doi:10.1016/j.tips.2018.03.006

Cited by 213 publications

(159 citation statements)

References 71 publications

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“…The lack of potentiation at GABAA-Rs containing the α4, α6, or δ subunits supports the notion that all ligands bind to the DZP-specific BZ-sensitive site of GABAA-Rs [12]. …”

Section: Discussionmentioning

confidence: 53%

“…GABA A receptors (GABAA-Rs) are composed of multiple subunits (α, β, γ, δ, ε, θ, π, and ρ) assembled into pentamers [10] forming a chloride channel. Benzodiazepines (BZs; such as diazepam, DZP) and imidazobenzodiazepines (IBZDs; such as flumazenil) represent the well-established classes of therapeutics [11] acting on GABAA-Rs [12]. BZs are prescribed to alleviate the burden of anxiety [13] but have debatable efficacy on the core symptoms of depression [14].…”

Section: Introductionmentioning

confidence: 99%

“…BZs are prescribed to alleviate the burden of anxiety [13] but have debatable efficacy on the core symptoms of depression [14]. BZs modulate GABAA-R activity as non-selective positive allosteric modulators (PAMs), via binding between the γ2 and either the α1, α2, α3, or α5 subunits [12]. Even though the beneficial effects of BZ seems to be mediated by their complex activity at multiple α subunits, this broad receptor activity contributes to significant side effects (sedation, hypnosis, ataxia, dependence, amnesia) limiting their therapeutic potential.…”

Section: Introductionmentioning

confidence: 99%

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Novel Benzodiazepine-Like Ligands with Various Anxiolytic, Antidepressant, or Pro-Cognitive Profiles

Prevot¹,

Vidojević

et al. 2019

Complex Psychiatry

124

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Altered gamma-aminobutyric acid (GABA) function is consistently reported in psychiatric disorders, normal aging, and neurodegenerative disorders and reduced function of GABA interneurons is associated with both mood and cognitive symptoms. Benzodiazepines (BZ) have broad anxiolytic, but also sedative, anticonvulsant and amnesic effects, due to nonspecific GABA-A receptor (GABAA-R) targeting. Varying the profile of activity of BZs at GABAA-Rs is predicted to uncover additional therapeutic potential. We synthesized four novel imidazobenzodiazepine (IBZD) amide ligands and tested them for positive allosteric modulation at multiple α-GABAA-R (α-positive allosteric modulators), pharmacokinetic properties, as well as anxiolytic and antidepressant activities in adult mice. Efficacy at reversing stress-induced or age-related working memory deficits was assessed using a spontaneous alternation task. Diazepam (DZP) was used as a control. Three ligands (GL-II-73, GL-II-74, and GL-II-75) demonstrated adequate brain penetration and showed predictive anxiolytic and antidepressant efficacies. GL-II-73 and GL-II-75 significantly reversed stress-induced and age-related working memory deficits. In contrast, DZP displayed anxiolytic but no antidepressant effects or effects on working memory. We demonstrate distinct profiles of anxiolytic, antidepressant, and/or pro-cognitive activities of newly designed IBZD amide ligands, suggesting novel therapeutic potential for IBZD derivatives in depression and aging.

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“…The lack of potentiation at GABAA-Rs containing the α4, α6, or δ subunits supports the notion that all ligands bind to the DZP-specific BZ-sensitive site of GABAA-Rs [12]. …”

Section: Discussionmentioning

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Novel Benzodiazepine-Like Ligands with Various Anxiolytic, Antidepressant, or Pro-Cognitive Profiles

Prevot¹,

Vidojević

et al. 2019

Complex Psychiatry

124

View full text Add to dashboard Cite

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“…The authors examined the effects of two weeks of social isolation on the brains and behaviour of male mice (equivalent to more than a year in these conditions for humans 4 ). First, the researchers used an array of behavioural tests to compare mice kept in isolation with control mice that had been housed in groups.…”

Section: Social Isolation's Molecular Signaturementioning

confidence: 99%

“…In the late nineteenth century, the Hungarian physicist Roland von Eötvös devoted years to verifying that the accelerations of various laboratory materials in Earth's gravitational field differ by less than a few parts per billion 3 . His modern-day successors, the Eöt-Wash group 4 in Seattle, Washington, pushed this bound to parts per 10 13 . And, in 2017, data from the French space mission MICROSCOPE 5 moved the goalpost by a further factor of ten.…”

Section: Elevated Fear Responsementioning

confidence: 99%

A molecular signature for social isolation identified in the brain

Zilkha¹,

Kimchi²

2018

Nature

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Chloride Channels

Akabas¹

2020

Encyclopedia of Life Sciences

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Chloride channels are integral membrane proteins that regulate the movement of chloride ions across cellular membranes. They perform a vital role in physiological processes such as epithelial transport, the regulation of nerve and muscle cell membrane excitability, cell volume regulation and in determining the pH within cytoplasmic membrane‐bound organelles. Several distinct protein families form chloride channels whose opening is regulated by different stimuli including neurotransmitter binding, changes in the concentrations of intracellular second messengers including cAMP and Ca 2+ , and phosphorylation. High‐resolution protein structures of many types of chloride channels have been solved by x‐ray crystallography and cryo‐electron microscopy. Mutations in genes encoding chloride channels impair their function and cause a variety of genetic diseases. Several clinically useful medicines act by modulating the activity of specific types of chloride channels. Key Concepts Chloride channels are ion channels that facilitate the movement of chloride ions across cell membranes. Chloride channels play fundamental roles in diverse physiological processes. Several distinct gene families encode proteins that function as chloride channels and have unique atomic structures. Genetic diseases result due to mutations in chloride channels that impair their function. The mechanism of action of a number of drugs used clinically involves chloride channels as specific targets.

show abstract

The Benzodiazepine Binding Sites of GABAA Receptors

Cited by 213 publications

References 71 publications

Novel Benzodiazepine-Like Ligands with Various Anxiolytic, Antidepressant, or Pro-Cognitive Profiles

Novel Benzodiazepine-Like Ligands with Various Anxiolytic, Antidepressant, or Pro-Cognitive Profiles

A molecular signature for social isolation identified in the brain

Chloride Channels

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