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Br J Pharmacol
2004 May 01;1421:97-106. doi: 10.1038/sj.bjp.0705689.
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Salicylidene salicylhydrazide, a selective inhibitor of beta 1-containing GABAA receptors.
Thompson SA
,
Wheat L
,
Brown NA
,
Wingrove PB
,
Pillai GV
,
Whiting PJ
,
Adkins C
,
Woodward CH
,
Smith AJ
,
Simpson PB
,
Collins I
,
Wafford KA
.
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1. A high-throughput assay utilizing the voltage/ion probe reader (VIPR) technology identified salicylidene salicylhydrazide (SCS) as being a potent selective inhibitor of alpha2beta1gamma1 GABA(A) receptors with a maximum inhibition of 56+/-5% and an IC(50) of 32 (23, 45) nm. 2. Evaluation of this compound using patch-clamp electrophysiological techniques demonstrated that the compound behaved in a manner selective for receptors containing the beta1 subunit (e.g. maximum inhibition of 68.1+/-2.7% and IC(50) value of 5.3 (4.4, 6.5) nm on alpha2beta1gamma1 receptors). The presence of a beta1 subunit was paramount for the inhibition with changes between alpha1 and alpha2, gamma1 and gamma2, and the presence of a subunit having little effect. 3. On all subtypes, SCS produced incomplete inhibition with the greatest level of inhibition at alpha1beta1gamma1 receptors (74.3+/-1.4%). SCS displayed no use or voltage dependence, suggesting that it does not bind within the channel region. Concentration - response curves to GABA in the presence of SCS revealed a reduction in the maximum response with no change in the EC(50) or Hill coefficient. In addition, SCS inhibited pentobarbitone-induced currents. 4. Threonine 255, located within transmembrane domain (TM) 1, and isoleucine 308, located extracellularly just prior to TM3, were required for inhibition by SCS. 5. SCS did not compete with the known allosteric modulators, picrotoxin, pregnenolone sulphate, dehydroepiandrosterone 3-sulphate, bicuculline, loreclezole or mefenamic acid. Neither was the inhibition by SCS influenced by the benzodiazepine site antagonist flumazenil. 6. In conclusion, SCS is unique in selectively inhibiting GABA(A) receptors containing the beta1 subunit via an allosteric mechanism. The importance of threonine 255 and isoleucine 308 within the beta1 subunit and the lack of interaction with a range of GABA(A) receptor modulators suggests that SCS is interacting at a previously unidentified site.
Adkins,
alpha4beta3delta GABA(A) receptors characterized by fluorescence resonance energy transfer-derived measurements of membrane potential.
2001, Pubmed
Adkins,
alpha4beta3delta GABA(A) receptors characterized by fluorescence resonance energy transfer-derived measurements of membrane potential.
2001,
Pubmed
Ainscough,
Cytotoxicity of salicylaldehyde benzoylhydrazone analogs and their transition metal complexes: quantitative structure-activity relationships.
1999,
Pubmed
Barish,
A transient calcium-dependent chloride current in the immature Xenopus oocyte.
1983,
Pubmed
,
Xenbase
Belelli,
The interaction of the general anesthetic etomidate with the gamma-aminobutyric acid type A receptor is influenced by a single amino acid.
1997,
Pubmed
,
Xenbase
Bera,
GABA(A) receptor M2-M3 loop secondary structure and changes in accessibility during channel gating.
2002,
Pubmed
Blanton,
Identifying the lipid-protein interface of the Torpedo nicotinic acetylcholine receptor: secondary structure implications.
1994,
Pubmed
Brown,
Pharmacological characterization of a novel cell line expressing human alpha(4)beta(3)delta GABA(A) receptors.
2002,
Pubmed
Chang,
Stoichiometry of a recombinant GABAA receptor.
1996,
Pubmed
,
Xenbase
Farrar,
Stoichiometry of a ligand-gated ion channel determined by fluorescence energy transfer.
1999,
Pubmed
Hadingham,
Role of the beta subunit in determining the pharmacology of human gamma-aminobutyric acid type A receptors.
1993,
Pubmed
,
Xenbase
Hadingham,
Cloning of cDNA sequences encoding human alpha 2 and alpha 3 gamma-aminobutyric acidA receptor subunits and characterization of the benzodiazepine pharmacology of recombinant alpha 1-, alpha 2-, alpha 3-, and alpha 5-containing human gamma-aminobutyric acidA receptors.
1993,
Pubmed
Halliwell,
Subunit-selective modulation of GABAA receptors by the non-steroidal anti-inflammatory agent, mefenamic acid.
1999,
Pubmed
,
Xenbase
Hill-Venning,
Subunit-dependent interaction of the general anaesthetic etomidate with the gamma-aminobutyric acid type A receptor.
1997,
Pubmed
,
Xenbase
Jurd,
General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit.
2003,
Pubmed
Korpi,
Drug interactions at GABA(A) receptors.
2002,
Pubmed
Pirker,
GABA(A) receptors: immunocytochemical distribution of 13 subunits in the adult rat brain.
2000,
Pubmed
Pistis,
Complementary regulation of anaesthetic activation of human (alpha6beta3gamma2L) and Drosophila (RDL) GABA receptors by a single amino acid residue.
1999,
Pubmed
,
Xenbase
Reynolds,
Sedation and anesthesia mediated by distinct GABA(A) receptor isoforms.
2003,
Pubmed
Sieghart,
Subunit composition, distribution and function of GABA(A) receptor subtypes.
2002,
Pubmed
Smith,
Methodological approaches for the study of GABA(A) receptor pharmacology and functional responses.
2003,
Pubmed
Thompson,
Tracazolate reveals a novel type of allosteric interaction with recombinant gamma-aminobutyric acid(A) receptors.
2002,
Pubmed
,
Xenbase
Thompson,
Barbiturate interactions at the human GABAA receptor: dependence on receptor subunit combination.
1996,
Pubmed
,
Xenbase
Thompson,
Residues in transmembrane domains I and II determine gamma-aminobutyric acid type AA receptor subtype-selective antagonism by furosemide.
1999,
Pubmed
,
Xenbase
Wafford,
A novel allosteric modulatory site on the GABAA receptor beta subunit.
1994,
Pubmed
,
Xenbase
White,
Human alpha and beta subunits contribute to the EC50 for GABA at the GABAA receptor expressed in Xenopus oocytes.
1995,
Pubmed
,
Xenbase
Whiting,
GABA-A receptor subtypes in the brain: a paradigm for CNS drug discovery?
2003,
Pubmed
Wilkins,
Redox modulation of GABAA receptors obscured by Zn2+ complexation.
2002,
Pubmed
Wingrove,
The modulatory action of loreclezole at the gamma-aminobutyric acid type A receptor is determined by a single amino acid in the beta 2 and beta 3 subunit.
1994,
Pubmed
,
Xenbase
