Exploring the Orthosteric Binding Site of the γ-Aminobutyric Acid Type A Receptor Using 4-(Piperidin-4-yl)-1-hydroxypyrazoles 3- or 5-Imidazolyl Substituted: Design, Synthesis, and Pharmacological Evaluation

2013 ◽  
Vol 56 (16) ◽  
pp. 6536-6540 ◽  
Author(s):  
Jacob Krall ◽  
Claus H. Jensen ◽  
Troels E. Sørensen ◽  
Birgitte Nielsen ◽  
Anders A. Jensen ◽  
...  
Keyword(s):  
Binding Site ◽  
Type A ◽  
Aminobutyric Acid ◽  
Design Synthesis ◽  
Pharmacological Evaluation ◽  
Acid Type

Design, Synthesis, and Pharmacological Evaluation of Novel β2/3 Subunit-Selective γ-Aminobutyric Acid Type A (GABAA) Receptor Modulators

2018 ◽  
Vol 62 (1) ◽  
pp. 317-341 ◽  
Author(s):  
Marco Stadler ◽  
Serena Monticelli ◽  
Thomas Seidel ◽  
Denise Luger ◽  
Isabella Salzer ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Type A ◽  
Aminobutyric Acid ◽  
Design Synthesis ◽  
Pharmacological Evaluation ◽  
Acid Type ◽  
Receptor Modulators

Structural elements involved in activation of the γ-aminobutyric acid type A (GABAA) receptor

2004 ◽  
Vol 32 (3) ◽  
pp. 540-546 ◽  
Author(s):  
T.L. Kash ◽  
J.R. Trudell ◽  
N.L. Harrison
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Binding Site ◽  
Type A ◽  
Aminobutyric Acid ◽  
Structural Elements ◽  
Agonist Binding ◽  
Acid Type ◽  
Gated Ion Channels ◽  
Ligand Gated Ion Channels

Ligand-gated ion channels function as rapid signal transducers, converting chemical signals (in the form of neurotransmitters) into electrical signals in the postsynaptic neuron. This is achieved by the recognition of neurotransmitter at its specific-binding sites, which then triggers the opening of an ion channel (‘gating’). For this to occur rapidly (<1 ms), there must be an efficient coupling between the agonist-binding site and the gate, located more than 30 Å (1 Å=0.1 nm) away. Whereas a great deal of progress has been made in elucidating the structure and function of both the agonist-binding site and the ion permeation pathway in ligand-gated ion channels, our knowledge of the coupling mechanism between these domains has been limited. In this review, we summarize recent studies of the agonist-binding site and the ion channel in the γ-aminobutyric acid type A receptor, and discuss those structural elements that may mediate coupling between them. We will also consider some possible molecular mechanisms of receptor activation.

scholarly journals Proximity-accelerated Chemical Coupling Reaction in the Benzodiazepine-binding Site of γ-Aminobutyric Acid Type A Receptors

2007 ◽  
Vol 282 (36) ◽  
pp. 26316-26325 ◽  
Author(s):  
Kelly R. Tan ◽  
Anne Gonthier ◽  
Roland Baur ◽  
Margot Ernst ◽  
Maurice Goeldner ◽  
...  
Keyword(s):  
Binding Site ◽  
Coupling Reaction ◽  
Type A ◽  
Aminobutyric Acid ◽  
Acid Type ◽  
Benzodiazepine Binding ◽  
Chemical Coupling

5-(Piperidin-4-yl)-3-Hydroxypyrazole: A Novel Scaffold for Probing the Orthosteric γ-Aminobutyric Acid Type A Receptor Binding Site

ChemMedChem ◽  
2014 ◽  
Vol 9 (11) ◽  
pp. 2475-2485 ◽  
Author(s):  
Jacob Krall ◽  
Kenneth T. Kongstad ◽  
Birgitte Nielsen ◽  
Troels E. Sørensen ◽  
Thomas Balle ◽  
...  
Keyword(s):  
Binding Site ◽  
Receptor Binding ◽  
Type A ◽  
Aminobutyric Acid ◽  
Receptor Binding Site ◽  
Acid Type ◽  
Novel Scaffold

scholarly journals A Conserved Tyrosine in the β2Subunit M4 Segment Is a Determinant of γ-Aminobutyric Acid Type A Receptor Sensitivity to Propofol

2007 ◽  
Vol 107 (3) ◽  
pp. 412-418 ◽  
Author(s):  
James E. Richardson ◽  
Paul S. Garcia ◽  
Kate K. O'Toole ◽  
Jason M. C. Derry ◽  
Shannon V. Bell ◽  
...  
Keyword(s):  
Binding Site ◽  
Type A ◽  
Receptor Activation ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
General Anesthetics ◽  
Receptor Function ◽  
293 Cells ◽  
Acid Type ◽  
Normal Sensitivity

Background The gamma-aminobutyric acid type A receptor (GABAA-R) beta subunits are critical targets for the actions for several intravenous general anesthetics, but the precise nature of the anesthetic binding sites are unknown. In addition, little is known about the role the fourth transmembrane (M4) segment of the receptor plays in receptor function. The aim of this study was to better define the propofol binding site on the GABAA-R by conducting a tryptophan scan in the M4 segment of the beta2 subunit. Methods Seven tryptophan mutations were introduced into the C-terminal end of the M4 segment of the GABAA-R beta2 subunit. GABAA-R subunit complementary DNAs were transfected into human embryonic kidney 293 cells grown on glass coverslips. After transfection (36-72 h), coverslips were transferred to a perfusion chamber to assay receptor function. Cells were whole cell patch clamped and exposed to GABA, propofol, etomidate, and pregnenolone. Chemicals were delivered to the cells using two 10-channel infusion pumps and a rapid solution exchanger. Results All tryptophan mutations were well tolerated, and with one exception, all resulted in minimal changes in receptor activation by GABA. One mutation, beta2(Y444W), selectively suppressed the ability of propofol to enhance receptor function while retaining normal sensitivity to etomidate and pregnenolone. Conclusions This is the first report of a mutation that selectively reduces propofol sensitivity without altering the action of etomidate. The reduction in propofol sensitivity is consistent with the loss of a hydrogen bond within the propofol binding site. These results also suggest a possible orientation of the propofol molecule within its binding site.

scholarly journals Gephyrin-mediated γ-Aminobutyric Acid Type A and Glycine Receptor Clustering Relies on a Common Binding Site

2011 ◽  
Vol 286 (49) ◽  
pp. 42105-42114 ◽  
Author(s):  
Hans-Michael Maric ◽  
Jayanta Mukherjee ◽  
Verena Tretter ◽  
Stephen J. Moss ◽  
Hermann Schindelin
Keyword(s):  
Binding Site ◽  
Glycine Receptor ◽  
Type A ◽  
Aminobutyric Acid ◽  
Receptor Clustering ◽  
Acid Type

scholarly journals Mapping General Anesthetic Binding Site(s) in Human α1β3 γ-Aminobutyric Acid Type A Receptors with [3H]TDBzl-Etomidate, a Photoreactive Etomidate Analogue

Biochemistry ◽  
2012 ◽  
Vol 51 (4) ◽  
pp. 836-847 ◽  
Author(s):  
David C. Chiara ◽  
Zuzana Dostalova ◽  
Selwyn S. Jayakar ◽  
Xiaojuan Zhou ◽  
Keith W. Miller ◽  
...  
Keyword(s):  
Binding Site ◽  
Type A ◽  
Aminobutyric Acid ◽  
General Anesthetic ◽  
Acid Type
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