PMID: 9658187Jul 11, 1998Paper

Photoaffinity labeling of the benzodiazepine binding site of alpha1beta3gamma2 gamma-aminobutyric acidA receptors with flunitrazepam identifies a subset of ligands that interact directly with His102 of the alpha subunit and predicts orientation of these within the benzodiazepine pharmacophore

Molecular Pharmacology
R M McKernanH Broughton

Abstract

Photoincorporation of ligands into the benzodiazepine site of native gamma-aminobutyric acidA (GABAA) receptors provides useful information about the nature of the benzodiazepine (BZ) binding site. Photoincorporation of flunitrazepam into a single population of GABAA receptors, recombinant human alpha1beta3gamma2, was investigated to probe further the mechanism and orientation of flunitrazepam and other ligands in the BZ binding site. It was concluded that the receptor is primarily derivatized with the entire, unfragmented, flunitrazepam molecule, which undergoes a conformational change during photolysis and largely vacates the benzodiazepine binding site. Investigation of the BZ site after photoincorporation of [3H]flunitrazepam confirmed that binding of other radioligands was unaffected by incorporation of flunitrazepam. This did not correlate with their efficacy but depended on the presence of particular structural features in the molecule. It was observed that affected compounds have a pendant phenyl moiety, analogous to the 5-phenyl group of flunitrazepam, which are proposed to overlap and interact with the same residue or residues in the BZ binding site. Because the major site of flunitrazepam photoincorporation has been ...Continue Reading

References

Jul 15, 1992·Proceedings of the National Academy of Sciences of the United States of America·K L HadinghamP J Whiting
Feb 15, 1991·Proceedings of the National Academy of Sciences of the United States of America·D B Pritchett, P H Seeburg
Apr 2, 1985·European Journal of Pharmacology·T T GibbsD H Farb
Jun 15, 1984·European Journal of Pharmacology·H MöhlerW Hunkeler
Apr 8, 1983·European Journal of Pharmacology·W SieghartG Drexler
May 1, 1995·Trends in Pharmacological Sciences·G B Smith, R W Olsen
Aug 15, 1995·The Biochemical Journal·F A Stephenson
Feb 1, 1993·Journal of Computer-aided Molecular Design·Y C MartinP A Pavlik
Jul 15, 1993·European Journal of Pharmacology·L L Duncalfe, S M Dunn
Apr 1, 1996·Trends in Neurosciences·R M McKernan, P J Whiting
Nov 30, 1995·European Journal of Pharmacology·K L HadinghamP J Whiting
Mar 18, 1996·European Journal of Pharmacology·L L Duncalfe, S M Dunn
Aug 5, 1997·Proceedings of the National Academy of Sciences of the United States of America·A Buhr, E Sigel
Jan 14, 1998·Trends in Pharmacological Sciences·E Sigel, A Buhr

❮ Previous
Next ❯

Citations

Oct 3, 2006·Molecular Pharmacology·Feyza SancarCynthia Czajkowski
Feb 17, 2015·Future Medicinal Chemistry·Ewan Smith, Ian Collins
Sep 21, 2010·Quarterly Reviews of Biophysics·Andrew J ThompsonSarah C R Lummis
Jul 6, 2016·Frontiers in Molecular Neuroscience·Roshan PuthenkalamMargot Ernst
Jul 26, 2017·Scientific Reports·Cecilia M BorgheseBoris Tabakoff
Nov 13, 2003·The Journal of Biological Chemistry·Dmytro BerezhnoyErwin Sigel
Feb 28, 2002·European Journal of Pharmacology·Peter B WingrovePaul J Whiting
Apr 21, 1999·Brain Research. Brain Research Reviews·A K Mehta, M K Ticku
Jun 19, 2002·Trends in Biochemical Sciences·Brett A CromerMichael W Parker
Aug 1, 2006·Journal of Molecular Graphics & Modelling·Valérie Campagna-Slater, Donald F Weaver
Feb 6, 2004·Journal of Medicinal Chemistry·Ajay N Jain

❮ Previous
Next ❯

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.