Structural requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A (GABAA) receptor are different.
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.
Hanson
Susan M
SM
Department of Physiology and Program in Molecular and Cellular Pharmacology, University of Wisconsin Madison, Madison, Wisconsin 53711, USA.
Morlock
Elaine V
EV
Satyshur
Kenneth A
KA
Czajkowski
Cynthia
C
D053961:Azabicyclo Compounds / Q000737:chemistry* / Q000378:metabolism*; D001569:Benzodiazepines / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D002460:Cell Line; D003198:Computer Simulation; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D000069582:Eszopiclone; D058785:GABA-A Receptor Agonists; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D010879:Piperazines / Q000737:chemistry* / Q000378:metabolism*; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D000077334:Zolpidem
D053961:Azabicyclo Compounds; D058785:GABA-A Receptor Agonists; D008024:Ligands; D010879:Piperazines; D011725:Pyridines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D000077334:Zolpidem; D003545:Cysteine; D000069582:Eszopiclone