Paper
Structural Determinants for High-Affinity Zolpidem Binding to GABA-A receptors
Published Jan 1, 2007 · J. A. Teissére, Feyza Sancar, C. Czajkowski
Molecular Pharmacology
63
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2
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Abstract
The imidazopyridine zolpidem (Ambien) is one of the most commonly prescribed sleep aids in the United States (Rush, 1998). Similar to classic benzodiazepines (BZDs), zolpidem binds at the extracellular N-terminal α/γ subunit interface of the GABA-A receptor (GABAR). However, zolpidem differs significantly from classic BZDs in chemical structure and neuropharmacological properties. Thus, classic BZDs and zolpidem are likely to have different requirements for high-affinity binding to GABARs. To date, three residues—γ2Met57, γ2Phe77, and γ2Met130—have been identified as necessary for high-affinity zolpidem binding (Proc Natl Acad Sci USA 94:8824-8829, 1997; Mol Pharmacol 52:874-881, 1997). In this study, we used radioligand binding techniques, γ2/α1 chimeric subunits (χ), site-directed mutagenesis, and molecular modeling to identify additional γ2 subunit residues important for high-affinity zolpidem binding. Whereas α1β2χ receptors containing only the first 161 amino-terminal residues of the γ2 subunit bind the classic BZD flunitrazepam with wild-type affinity, zolpidem affinity is decreased ∼8-fold. By incrementally restoring γ2 subunit sequence, we identified a seven-amino acid stretch in the γ2 subunit loop F region (amino acids 186-192) that is required to confer high-affinity zolpidem binding to GABARs. When mapped to a homology model, these seven amino acids make up part of loop F located at the α/γ interface. Based on in silico zolpidem docking, three residues within loop F, γ2Glu189, γ2Thr193, and γ2Arg194, emerge as being important for stabilizing zolpidem in the BZD binding pocket and probably interact with other loop F residues to maintain the structural integrity of the BZD binding site.
In Vitro StudyA seven-amino acid stretch in the 2 subunit loop F region is crucial for high-affinity zolpidem binding to GABA-A receptors, potentially impacting its neuropharmacological properties.
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