Developing dual functional allosteric modulators of GABAA receptors

Liu, Xiaodong F.; Chang, Huifang; Schmiesing, Richard J.; Wesolowski, Steven S.; Knappenberger, Katharine S.; Arriza, Jeffrey L.; Chapdelaine, Marc J.

doi:10.1016/j.bmc.2010.09.058

Cited by 10 publications

(4 citation statements)

References 29 publications

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“…The computed barriers provide a reasonable means for prospective molecular designs such that the resulting compounds either have essentially free rotation or are locked into a single atropisomer with an exceedingly slow interconversion rate. 8,9…”

Section: Resultsmentioning

confidence: 99%

“…The γ-aminobutyric acid (GABA) modulators in the present study are designed as potential anxiolytics for psychiatric indications. 8,9 The compounds contain a biphenyl substructure and may exhibit atropisomerism depending on the size and nature of the substituents. In addition to the quantification of chiral stability, the assignment of absolute axial stereochemistry is desirable to differentiate the biological activities of the individual atropisomers (i.e., if only one of the atropisomers is biologically active, which one is it and can structure-activity relationships be established?).…”

Section: Introductionmentioning

confidence: 99%

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Vibrational Circular Dichroism (VCD) Chiral Assignment of Atropisomers: Application to γ-Aminobutyric Acid (GABA) Modulators Designed as Potential Anxiolytic Drugs

Pivonka

Wesolowski

2013

Appl Spectrosc

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Atropisomers exist when axial chirality is present as a result of conformationally restricted rotation around a single bond. The interconversion rate of the individual atropisomers is critical to the assessment of chiral stability of a drug throughout scale-up, development, production, and storage as well as in vivo pharmacokinetics. We describe the application of vibrational circular dichroism spectroscopy coupled with quantum mechanics simulations to assign the absolute axial chirality and measure the racemization half-life of a series of potential anxiolytic drugs that act as γ-aminobutyric acid modulators.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Vibrational Circular Dichroism (VCD) Chiral Assignment of Atropisomers: Application to γ-Aminobutyric Acid (GABA) Modulators Designed as Potential Anxiolytic Drugs

Pivonka

Wesolowski

2013

Appl Spectrosc

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“…Initial studies examining the GABA A R modulatory effects of cinnoline- (the prototypic example of which is ICI 198,256) and related quinoline-based compounds were halted due to the low bioavailability of these molecules, along with their potential to form reactive metabolites . However, these compounds were chosen by AstraZeneca as good starting points for their renewed interest in developing subtype-selective GABA A R modulators. , The exemplars of the cinnoline series and related quinoline structures ( 17 and 18 , Figure ) had high efficacy for α1-GABA A Rs while at the same time being metabolically unstable.…”

Section: α2/α3-gabaar Pamsmentioning

confidence: 99%

“…72 However, these compounds were chosen by AstraZeneca as good starting points for their renewed interest in developing subtype-selective GABA A R modulators. 72,73 The exemplars of the cinnoline series and related quinoline structures (17 and 18, Figure 7) had high efficacy for α1-GABA A Rs while at the same time being metabolically unstable.…”

Section: Introductionmentioning

confidence: 99%

Subtype Selective γ-Aminobutyric Acid Type A Receptor (GABA_AR) Modulators Acting at the Benzodiazepine Binding Site: An Update

et al. 2019

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γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter within the central nervous system (CNS) with fast, trans-synaptic and modulatory extrasynaptic effects being mediated by the ionotropic GABA Type A receptors (GABAARs). These receptors are of particular interest since they are the molecular target of a number of pharmacological agents, of which the benzodiazepines (BZDs), such as diazepam, are the best described. The anxiolytic, sedating and myorelaxant effects of BZDs are mediated by separate populations of GABAARs containing either α1, α2, α3 or α5 subunits and the molecular dissection of the pharmacology of BZDs indicates that subtype-selective GABAAR modulators will have novel pharmacological profiles. This is best exemplified by α2/α3-GABAAR positive allosteric modulators (PAMs) and α5-GABAAR negative allosteric modulators (NAMs), which were originally developed as non-sedating anxiolytics and cognition enhancers, respectively. This review aims to summarize the current state of the field of subtype-selective GABAAR modulators acting via the BZD binding site and their potential clinical indications. Recently, high-resolution cryo-electron microscopy (cryo-EM) structures of the human α1β2γ2 and α1β3γ2 GABAARs have been reported. 11,12,19 The analysis of the receptors in complexes with the orthosteric agonist GABA and the GABA binding site antagonist bicuculline as well as the openchannel blocker pycrotoxin and BZD binding site ligands such as diazepam (Figure 1), alprazolam and flumazenil not only provide a detailed insight into the overall assembly and heteromeric interactions of GABAARs, but have also started to reveal the structural basis of receptor activation and allosteric modulation. The focus of the present review will be on compounds that bind to the BZD site with more detailed descriptions regarding the other GABAAR binding sites being available elsewhere. 14,15,20,21

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Rational approaches for the design of various GABA modulators and their clinical progression

et al. 2020

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Developing dual functional allosteric modulators of GABAA receptors

Cited by 10 publications

References 29 publications

Vibrational Circular Dichroism (VCD) Chiral Assignment of Atropisomers: Application to γ-Aminobutyric Acid (GABA) Modulators Designed as Potential Anxiolytic Drugs

Vibrational Circular Dichroism (VCD) Chiral Assignment of Atropisomers: Application to γ-Aminobutyric Acid (GABA) Modulators Designed as Potential Anxiolytic Drugs

Subtype Selective γ-Aminobutyric Acid Type A Receptor (GABA_AR) Modulators Acting at the Benzodiazepine Binding Site: An Update

Rational approaches for the design of various GABA modulators and their clinical progression

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Developing dual functional allosteric modulators of GABAA receptors

Cited by 10 publications

References 29 publications

Vibrational Circular Dichroism (VCD) Chiral Assignment of Atropisomers: Application to γ-Aminobutyric Acid (GABA) Modulators Designed as Potential Anxiolytic Drugs

Vibrational Circular Dichroism (VCD) Chiral Assignment of Atropisomers: Application to γ-Aminobutyric Acid (GABA) Modulators Designed as Potential Anxiolytic Drugs

Subtype Selective γ-Aminobutyric Acid Type A Receptor (GABAAR) Modulators Acting at the Benzodiazepine Binding Site: An Update

Rational approaches for the design of various GABA modulators and their clinical progression

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Product

Resources

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Subtype Selective γ-Aminobutyric Acid Type A Receptor (GABA_AR) Modulators Acting at the Benzodiazepine Binding Site: An Update