Allosteric GABAA Receptor Modulators—A Review on the Most Recent Heterocyclic Chemotypes and Their Synthetic Accessibility

Alanis, Blanca Angelica Vega; Iorio, Maria Teresa; Silva, Luca; Bampali, Konstantina; Ernst, Margot; Schnürch, Michael; Mihovilovic, Marko D.

doi:10.3390/molecules25040999

Cited by 24 publications

(17 citation statements)

References 148 publications

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“…The pyrazoloquinolinones (PQs) exhibit high potential as both non-sedative anxiolytics and as benzodiazepine antagonists (Savini et al, 2001;Vega Alanis et al, 2020) and, as such, represent interesting chemotypes. PQs exhibit features of both "continuous" and "discontinuous" SARs, depending on the corresponding substitution sites over the scaffold.…”

Section: Introductionmentioning

confidence: 99%

Demystifying the Molecular Basis of Pyrazoloquinolinones Recognition at the Extracellular α1+/β3- Interface of the GABAA Receptor by Molecular Modeling

Singh

Villoutreix

2020

Front. Pharmacol.

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GABA A receptors are pentameric ligand-gated ion channels that serve as major inhibitory neurotransmitter receptors in the mammalian brain and the target of numerous clinically relevant drugs interacting with different ligand binding sites. Here, we report an in silico approach to investigate the binding of pyrazoloquinolinones (PQs) that mediate allosteric effects through the extracellular a+/binterface of GABA A receptors. First, we docked a potent prototype of PQs into the a1+/b3site of a homology model of the human a1b3g2 subtype of the GABA A receptor. Next, for each docking pose, we computationally derived protein-ligand complexes for 18 PQ analogs with known experimental potency. Subsequently, binding energy was calculated for all complexes using the molecular mechanics-generalized Born surface area method. Finally, docking poses were quantitatively assessed in the light of experimental data to derive a binding hypothesis. Collectively, the results indicate that PQs at the a1+/b3site likely exhibit a common binding mode that can be characterized by a hydrogen bond interaction with b3Q64 and hydrophobic interactions involving residues a1F99, b3Y62, b3M115, a1Y159, and a1Y209. Importantly, our results are in good agreement with the recently resolved cryo-Electron Microscopy structures of the human a1b3g2 and a1b2g2 subtypes of GABA A receptors.

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Section: Introductionmentioning

confidence: 99%

Demystifying the Molecular Basis of Pyrazoloquinolinones Recognition at the Extracellular α1+/β3- Interface of the GABAA Receptor by Molecular Modeling

Singh

Villoutreix

2020

Front. Pharmacol.

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“…Historically, PQs have been developed as ligands of the high affinity benzodiazepine binding sites ( Iorio et al, 2020 ; Vega Alanis et al, 2020 ). In turn, a number of derivatives such as CGS 8216, CGS 9895, and others were used in pre-clinical research.…”

Section: Discussionmentioning

confidence: 99%

Structure-Guided Computational Methods Predict Multiple Distinct Binding Modes for Pyrazoloquinolinones in GABAA Receptors

et al. 2021

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Pyrazoloquinolinones (PQs) are a versatile class of GABAA receptor ligands. It has been demonstrated that high functional selectivity for certain receptor subtypes can be obtained by specific substitution patterns, but so far, no clear SAR rules emerge from the studies. As is the case for many GABAA receptor targeting chemotypes, PQs can interact with distinct binding sites on a given receptor pentamer. In pentamers of αβγ composition, such as the most abundant α1β2γ2 subtype, many PQs are high affinity binders of the benzodiazepine binding site at the extracellular α+/γ2− interfaces. There they display a functionally near silent, flumazenil-like allosteric activity. More recently, interactions with extracellular α+/β− interfaces have been investigated, where strong positive modulation can be steered toward interesting subtype preferences. The most prominent examples are functionally α6-selective PQs. Similar to benzodiazepines, PQs also seem to interact with sites in the transmembrane domain, mainly the sites used by etomidate and barbiturates. This promiscuity leads to potential contributions from multiple sites to net modulation. Developing ligands that interact exclusively with the extracellular α+/β− interfaces would be desired. Correlating functional profiles with binding sites usage is hampered by scarce and heterogeneous experimental data, as shown in our meta-analysis of aggregated published data. In the absence of experimental structures, bound states can be predicted with pharmacophore matching methods and with computational docking. We thus performed pharmacophore matching studies for the unwanted sites, and computational docking for the extracellular α1,6+/β3− interfaces. The results suggest that PQs interact with their binding sites with diverse binding modes. As such, rational design of improved ligands needs to take a complex structure-activity landscape with branches between sub-series of derivatives into account. We present a workflow, which is suitable to identify and explore potential branching points on the structure-activity landscape of any small molecule chemotype.

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“…Methylation at the 3β position of ganaxolone impairs its metabolism to inactive metabolites, thereby increasing its period of effectiveness in inhibiting seizures compared to allopregnanolone ( 26 ). Like allopregnanolone, ganaxolone is an allosteric modulator of GABA- A receptors and acts through different allosteric binding sites to that of benzodiazepines, as revealed by ligand binding assays and receptor mutational analysis ( 17 , 27 , 28 ).…”

Section: Protective Effects Of Neurosteroids Against Epileptic Seizurmentioning

confidence: 99%

“…One possible interpretation of the results is that these two neurosteroids do not occupy all the progesterone binding sites on mPRδ. However, additional research on their potential binding to allosteric sites as well as their interactions with progesterone binding to orthosteric sites will be required to determine the nature of their interactions with mPRδ, and whether, for example, they act as ago-allosteric ligands ( 28 , 53 , 54 ). The results indicate that ganaxolone, like allopregnanolone, can potentially influence progesterone signaling through mPRδ.…”

Section: Interactions Of Ganaxolone With Mprsmentioning

confidence: 99%

Anti-apoptotic Actions of Allopregnanolone and Ganaxolone Mediated Through Membrane Progesterone Receptors (PAQRs) in Neuronal Cells

Thomas¹,

Pang²

2020

Front. Endocrinol.

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Allosteric GABAA Receptor Modulators—A Review on the Most Recent Heterocyclic Chemotypes and Their Synthetic Accessibility

Cited by 24 publications

References 148 publications

Demystifying the Molecular Basis of Pyrazoloquinolinones Recognition at the Extracellular α1+/β3- Interface of the GABAA Receptor by Molecular Modeling

Demystifying the Molecular Basis of Pyrazoloquinolinones Recognition at the Extracellular α1+/β3- Interface of the GABAA Receptor by Molecular Modeling

Structure-Guided Computational Methods Predict Multiple Distinct Binding Modes for Pyrazoloquinolinones in GABAA Receptors

Anti-apoptotic Actions of Allopregnanolone and Ganaxolone Mediated Through Membrane Progesterone Receptors (PAQRs) in Neuronal Cells

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