Imperial College London
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Prof. William Wisden F. Med. Sci.

Faculty of Natural Sciences, Department of Life Sciences

Chair in Molecular Neuroscience
 
 
 
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Contact

 

+44 (0)20 7594 9744w.wisden Website CV

 
 
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Location

 

401BSir Ernst Chain BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Ogris:2004:10.1016/j.bcp.2004.07.020,
author = {Ogris, W and Pöltl, A and Hauer, B and Ernst, M and Oberto, A and Wulff, P and Höger, H and Wisden, W and Sieghart, W},
doi = {10.1016/j.bcp.2004.07.020},
journal = {Biochem Pharmacol},
pages = {1621--1629},
title = {Affinity of various benzodiazepine site ligands in mice with a point mutation in the GABA(A) receptor gamma2 subunit.},
url = {http://dx.doi.org/10.1016/j.bcp.2004.07.020},
volume = {68},
year = {2004}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - The benzodiazepine binding site of GABA(A) receptors is located at the interface of the alpha and gamma subunits. Certain point mutations in these subunits have been demonstrated to dramatically reduce the affinity of benzodiazepine binding site ligands for these receptors. Recently, mice were generated with a phenylalanine (F) to isoleucine (I) substitution at position 77 in the gamma2 subunit of GABA(A) receptors. Here we tested the potency of 24 benzodiazepine binding site ligands from 16 different structural classes for inhibition of [(3)H]flunitrazepam binding to brain membranes of these gamma2F77I mice. Results indicate that the potency of the classical 1,4-benzodiazepines, of the 1,4-thienodiazepine clotiazepam, the 1,5-benzodiazepine clobazam, or the pyrazoloquinoline CGS 9896 is only 2-7-fold reduced by this gamma2F77I point mutation. The potency of the imidazopyrimidines Ru 32698, Ru 33203, and Ru 33356, of the imidazoquinoline Ru 31719, or the pyrazolopyridine CGS 20625 is reduced 10-20-fold, whereas the potency of some imidazobenzodiazepines, beta-carbolines, cyclopyrrolones, imidazopyridines, triazolopyridazines, or quinolines is 100-1000-fold reduced. Interestingly, the extent of potency reduction induced by the gamma2F77I point mutation varied within the structural classes of compounds. Results support and significantly extend previous observations indicating that the residue gamma2F77 is important for high affinity binding of some, but not all benzodiazepine site ligands.
AU  - Ogris,W
AU  - Pöltl,A
AU  - Hauer,B
AU  - Ernst,M
AU  - Oberto,A
AU  - Wulff,P
AU  - Höger,H
AU  - Wisden,W
AU  - Sieghart,W
DO  - 10.1016/j.bcp.2004.07.020
EP  - 1629
PY  - 2004///
SN  - 0006-2952
SP  - 1621
TI  - Affinity of various benzodiazepine site ligands in mice with a point mutation in the GABA(A) receptor gamma2 subunit.
T2  - Biochem Pharmacol
UR  - http://dx.doi.org/10.1016/j.bcp.2004.07.020
UR  - https://www.ncbi.nlm.nih.gov/pubmed/15451405
VL  - 68
ER  -
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