Different Benzodiazepines Bind with Distinct Binding Modes to GABAA Receptors

ACS Chemical Biology
Alshaimaa A ElgarfPetra Scholze

Abstract

Benzodiazepines are clinically relevant drugs that bind to GABAA neurotransmitter receptors at the α+/γ2- interfaces and thereby enhance GABA-induced chloride ion flux leading to neuronal hyperpolarization. However, the structural basis of benzodiazepine interactions with their high-affinity site at GABAA receptors is controversially debated in the literature, and in silico studies led to discrepant binding mode hypotheses. In this study, computational docking of diazepam into α+/γ2- homology models suggested that a chiral methyl group, which is known to promote preferred binding to α5-containing GABAA receptors (position 3 of the seven-membered diazepine ring), could possibly provide experimental evidence that supports or contradicts the proposed binding modes. Thus, we investigated three pairs of R and S isomers of structurally different chemotypes, namely, diazepam, imidazobenzodiazepine, and triazolam derivatives. We used radioligand displacement studies as well as two-electrode voltage clamp electrophysiology in α1β3γ2-, α2β3γ2-, α3β3γ2-, and α5β3γ2-containing GABAA receptors to determine the ligand binding and functional activity of the three chemotypes. Interestingly, both imidazobenzodiazepine isomers displayed comparab...Continue Reading

References

Dec 5, 1993·Journal of Molecular Biology·A Sali, T L Blundell
Sep 23, 1997·Journal of Molecular Biology·S Jones, J M Thornton
Jan 16, 2003·Molecular Pharmacology·Amy M KuckenCynthia Czajkowski
Mar 30, 2007·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Miroslav M SavićJames M Cook
Jun 5, 2007·Journal of Molecular Graphics & Modelling·Younes MokrabP-L Chau
Jun 2, 2009·Molecular Pharmacology·D BerezhnoyD H Farb
Jan 21, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Joachim RamerstorferMargot Ernst
Jul 30, 2011·Nature Reviews. Drug Discovery·Uwe Rudolph, Frédéric Knoflach
Mar 27, 2012·Nature Chemical Biology·Lars RichterMargot Ernst
Mar 26, 2013·Expert Opinion on Therapeutic Patents·Gabriella Guerrini, Giovanna Ciciani
Oct 29, 2013·Annual Review of Pharmacology and Toxicology·Uwe Rudolph, Hanns Möhler
Jun 10, 2014·Nature·Paul S Miller, A Radu Aricescu
Jun 25, 2014·ACS Chemical Biology·Simon J MiddendorpErwin Sigel
Dec 18, 2014·JAMA Psychiatry·Mark OlfsonMichael Schoenbaum
Jan 21, 2015·Advances in Pharmacology·Werner Sieghart
Dec 19, 2015·International Journal of Medicinal Chemistry·Terry ClaytonJames M Cook
Jul 6, 2016·Frontiers in Molecular Neuroscience·Roshan PuthenkalamMargot Ernst

❮ Previous
Next ❯

Citations

May 22, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Yahya S Al-AwthanHafiz Ansar Rasul Suleria

❮ Previous
Next ❯

Software Mentioned

GOLD
MOE
MOE Builder
Modeller

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.