[3H]L-655,708, a Novel Ligand Selective for the Benzodiazepine Site of GABAA Receptors which Contain the α5 Subunit

  title={[3H]L-655,708, a Novel Ligand Selective for the Benzodiazepine Site of GABAA Receptors which Contain the $\alpha$5 Subunit},
  author={K. Quirk and P. Blurton and S. Fletcher and P. Leeson and F. Tang and D. Mellilo and C. Ragan and R. Mckernan},
A compound (L-655,708) has been identified which has at least 50-fold selectivity for the benzodiazepine site on GABAA receptors containing an alpha 5 subunit over those containing an alpha 1, alpha 2, alpha 3 or alpha 6 subunit in combination with beta 3 and gamma 2. The compound was radiolabelled with tritium and investigated as a novel radioligand which recognizes the benzodiazepine site of GABAA receptors which contain the alpha 5 subunit. [3H]L-655,708 labels one saturable and specific… Expand
In vivo labelling of α5 subunit-containing GABAA receptors using the selective radioligand [3H]L-655,708
L-655,708 is an imidazobenzodiazepine possessing 30-70-fold selectivity for the benzodiazepine binding site of GABA(A) receptors containing an alpha5 rather than alpha1, alpha2 or alpha3 subunit. InExpand
Evaluation of native GABAA receptors containing an α5 subunit
The type A receptor for γ-aminobutyric acid (GABA), or GABAA receptor, is a pentamer of highly variable quaternary structure. It includes two α subunits, drawn from a pool of six genes, which largelyExpand
Anxiogenic-like activity of L-655,708, a selective ligand for the benzodiazepine site of GABAA receptors which contain the alpha-5 subunit, in the elevated plus-maze test
GABAA receptor is a transmembrane hetero-oligomeric protein which consists of five subunits, the combination of which confers unique pharmacological properties to the receptor. L-655,708 is a newExpand
Synthesis of GABAA receptor agonists and evaluation of their alpha-subunit selectivity and orientation in the GABA binding site.
The results demonstrate the feasibility of synthesizing alpha subtype selective GABA mimetic drugs and weak agonists at alpha 2, alpha 3, and alpha 5-containing receptors. Expand
Evaluation of [methyl-3H]L655,708 and [ethyl-3H]RY80 as putative PET ligands for central GABA(A) receptors containing alpha5 subunit.
Despite the reasonable delivery to the brain, neither of the radioligands had sufficient retention in the tissues rich in alpha5-containing GABA(A) receptors to achieve a good selective signal. Expand
Rat and Human Hippocampal a 5 Subunit-Containing g-Aminobutyric AcidA Receptors Have a 5 b 3 g 2 Pharmacological Characteristics
The g-aminobutyric acid (GABA)A receptor is a hetero-oligomer consisting of five subunits, the combination of which confers unique pharmacological properties to the receptor. To understand theExpand
Affinity of various benzodiazepine site ligands in mice with a point mutation in the GABA(A) receptor gamma2 subunit.
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. Expand
Behavioral profile of L-655,708, a selective ligand for the benzodiazepine site of GABA-A receptors which contain the α5 subunit, in social encounters between male mice
GABA-A receptor is a transmembrane hetero-oligomeric protein which consists of five subunits, the combination of which confers unique pharmacological properties to the receptor. It is well-known thatExpand
The point mutation gamma 2F77I changes the potency and efficacy of benzodiazepine site ligands in different GABAA receptor subtypes.
Results indicate that the effects of the benzodiazepine site ligands zolpidem, zopiclone, Cl218872, L-655,708 and DMCM were nearly completely eliminated in all mutated receptors up to a 1 microM concentration, suggesting that the amino acid residue gamma 2F77 might also be involved in the transduction of the effect of Benzodiazepines from binding to gating. Expand
Rat and Human Hippocampal α5 Subunit-Containing γ-Aminobutyric AcidA Receptors Have α5β3γ2 Pharmacological Characteristics
Observations provide pharmacological and structural evidence for the prevalence of α5β3γ2 GABAA receptors in rat hippocampus, despite the clustering ofα5 and γ3 loci on the same chromosome. Expand


The pharmacology of the benzodiazepine site of the GABA-A receptor is dependent on the type of gamma-subunit present.
Data taken together suggest that the benzodiazepine site of the GABA-A receptor is formed with contributions from both the alpha and gamma-subunit, reflecting the presence of populations of receptors containing several different types of alpha-subunits. Expand
GABAA receptor subtypes immunopurified from rat brain with α subunit-specific antibodies have unique pharmacological properties
The majority of GABAA receptor oligomers contains only a single type of alpha subunit, and it is concluded that alpha 1, alpha 2, alpha 3, and alpha 5 subunits exist in vivo in combination with the beta subunit and gamma 2 subunit. Expand
Type I and type II GABAA-benzodiazepine receptors produced in transfected cells.
Diversity in benzodiazepine pharmacology is generated by heterogeneity of the alpha subunit of the GABAA receptor, indicating that there are subtypes within the type II class. Expand
Functional comparison of the role of gamma subunits in recombinant human gamma-aminobutyric acidA/benzodiazepine receptors.
It is demonstrated that unique pharmacological profiles can be conferred by receptors containing different gamma subunits, suggesting that some low efficacy partial agonists with gamma 2-containing receptors may be more efficacious with gamma 1- containing receptors. Expand
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.
The partial inverse agonist Ro15-4513 showed an approximately 10-15-fold higher affinity for alpha 5-containing than for alpha 1, alpha 1-, alpha 2, or alpha 3-containing receptors and is thus the first compound shown to have a significantlyHigher affinity for another receptor subtype than foralpha 1 beta 1 gamma 2. Expand
High affinity [3H]zolpidem binding in the rat brain: an imidazopyridine with agonist properties at central benzodiazepine receptors.
It is concluded that [3H]zolpidem possesses selectivity for B ZD receptors with the pharmacological characteristics and regional distribution of the BZD1 receptor subtype. Expand
Structure and pharmacology of vertebrate GABAA receptor subtypes.
How the techniques of molecular neurobiology enabled a revolution in the understanding of the GABAA receptor is described and how the roles played by individual subunits in the actions of many of these compounds are studied. Expand
γ‐Aminobutyric AcidA Receptor α5‐Subunit Creates Novel Type II Benzodiazepine Receptor Pharmacology
A cDNA encoding a protein with 70% amino acid identity to the previously characterized γ‐aminobutyric acidA (GABAA receptor α‐subunits) was isolated from a rat brain cDNA library by homology screening and a reclassification of the GABAA/benzodiazepine receptors is warranted. Expand
Mapping of GABAA receptor α5 and α6 subunit-like immunoreactivity in rat brain
The distribution of the α5 and α6 subunits of the GABAA receptor has been mapped in rat brain using affinity-purified antibodies generated against peptide sequences unique to the respective polypeptides to provide a further anatomical substrate for GAB AA receptor heterogeneity in the CNS. Expand
The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon
The expression patterns of 13 GABAA receptor subunit encoding genes (alpha 1-alpha 6, beta 1-beta 3, gamma 1-gamma 3, delta) were determined in adult rat brain by in situ hybridization. Each mRNAExpand