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Structural Determinants for High-Affinity Zolpidem Binding to GABA-A receptors

Department of Physiology (C.C., A.M.K, S.S.E), Neuroscience Training Program (C.C., F.S.), University of Wisconsin-Madison, Madison, Wisconsin; and Department of Biology, Muhlenberg College, Allentown, Pennsylvania (J.A.T.)

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 / 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—2Met57, 2Phe77, and 2Met130—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, 2/1 chimeric subunits (), site-directed mutagenesis, and molecular modeling to identify additional 2 subunit residues important for high-affinity zolpidem binding. Whereas 12 receptors containing only the first 161 amino-terminal residues of the 2 subunit bind the classic BZD flunitrazepam with wild-type affinity, zolpidem affinity is decreased 8-fold. By incrementally restoring 2 subunit sequence, we identified a seven-amino acid stretch in the 2 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 / interface. Based on in silico zolpidem docking, three residues within loop F, 2Glu189, 2Thr193, and 2Arg194, 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.

Address correspondence to: Cynthia Czajkowski, Department of Physiology, University of Wisconsin-Madison, 601 Science Dr, Madison, WI 53711. E-mail: czajkowski{at}physiology.wisc.edu

This article has been cited by other articles:

				S. M. Hanson and C. Czajkowski Structural Mechanisms Underlying Benzodiazepine Modulation of the GABAA Receptor J. Neurosci., March 26, 2008; 28(13): 3490 - 3499. [Abstract] [Full Text] [PDF]

				C. L. Padgett and S. C. R. Lummis The F-loop of the GABAA Receptor {gamma}2 Subunit Contributes to Benzodiazepine Modulation J. Biol. Chem., February 1, 2008; 283(5): 2702 - 2708. [Abstract] [Full Text] [PDF]