Structural Requirements for Eszopiclone and Zolpidem Binding to the γ-Aminobutyric Acid Type-A (GABAA) Receptor Are Different

被引:181
作者
Hanson, Susan M. [1 ]
Morlock, Elaine V. [2 ]
Satyshur, Kenneth A. [1 ]
Czajkowski, Cynthia [1 ,2 ]
机构
[1] Univ Wisconsin, Dept Physiol, Madison, WI 53711 USA
[2] Univ Wisconsin, Program Mol & Cellular Pharmacol, Madison, WI 53711 USA
关键词
D O I
10.1021/jm800889m
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The sleep-aids zolpidem and eszopiclone exert their effects by binding to and modulating gamma-aminobutyric acid type-A receptors (GABA(A)Rs), but little is known about the structural requirements for their actions. We made 24 cysteine mutations in the benzodiazepine (BZD) binding site of alpha(1)beta(2)gamma(2) GABA(A)Rs and measured zolpidem, eszopiclone, and BZD-site antagonist binding. Mutations in gamma(2)loop D and alpha(1)loops A and B altered the affinity of all ligands tested, indicating that these loops are important for BZD pocket structural integrity. In contrast, gamma(2)loop E and alpha(1)loop C mutations differentially affected ligand affinity, suggesting that these loops are important for ligand selectivity. In agreement with our mutagenesis data, eszopiclone docking yielded a single model stabilized by several hydrogen bonds. Zolpidem docking yielded three equally populated orientations with few polar interactions, suggesting that unlike eszopiclone, zolpidem relies more on shape recognition of the binding pocket than on specific residue interactions and may explain why zolpidem is highly alpha(1)- and gamma(2)-subunit selective.
引用
收藏
页码:7243 / 7252
页数:10
相关论文
共 54 条
  • [1] Two tyrosine residues on the alpha subunit are crucial for benzodiazepine binding and allosteric modulation of gamma-aminobutyric acid(A) receptors
    Amin, J
    BrooksKayal, A
    Weiss, DS
    [J]. MOLECULAR PHARMACOLOGY, 1997, 51 (05) : 833 - 841
  • [2] BALTER MB, 1992, J CLIN PSYCHIAT, V53, P34
  • [3] BENAVIDES J, 1992, J PHARMACOL EXP THER, V263, P884
  • [4] On the benzodiazepine binding pocket in GABAA receptors
    Berezhnoy, D
    Nyfeler, Y
    Gonthier, A
    Schwob, H
    Goeldner, M
    Sigel, E
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (05) : 3160 - 3168
  • [5] Molecular dissection of benzodiazepine binding and allosteric coupling using chimeric γ-aminobutyric acidA receptor subunits
    Boileau, AJ
    Kucken, AM
    Evers, AR
    Czajkowski, C
    [J]. MOLECULAR PHARMACOLOGY, 1998, 53 (02) : 295 - 303
  • [6] Residues at positions 206 and 209 of the alpha 1 subunit of gamma-aminobutyric acid(A) receptors influence affinities for benzodiazepine binding site ligands
    Buhr, A
    Schaerer, MT
    Baur, R
    Sigel, E
    [J]. MOLECULAR PHARMACOLOGY, 1997, 52 (04) : 676 - 682
  • [7] A point mutation in the gamma(2) subunit of gamma-aminobutyric acid type A receptors results in altered benzodiazepine binding site specificity
    Buhr, A
    Sigel, E
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (16) : 8824 - 8829
  • [8] Subtle changes in residue 77 of the gamma subunit of alpha 1 beta 2 gamma 2 GABA(A) receptors drastically alter the affinity for ligands of the benzodiazepine binding site
    Buhr, A
    Baur, R
    Sigel, E
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (18) : 11799 - 11804
  • [9] Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures
    Celie, PHN
    van Rossum-Fikkert, SE
    van Dijk, WJ
    Brejc, K
    Smit, AB
    Sixma, TK
    [J]. NEURON, 2004, 41 (06) : 907 - 914
  • [10] An updated unified pharmacophore model of the benzodiazepine binding site on γ-aminobutyric Acida receptors:: Correlation with comparative models
    Clayton, T.
    Chen, J. L.
    Ernst, M.
    Richter, L.
    Cromer, B. A.
    Morton, C. J.
    Ng, H.
    Kaczorowski, C. C.
    Helmstetter, F. J.
    Furtmueller, R.
    Ecker, G.
    Parker, M. W.
    Sieghart, W.
    Cook, J. M.
    [J]. CURRENT MEDICINAL CHEMISTRY, 2007, 14 (26) : 2755 - 2775