Structure-Activity Studies of 3,9-Diazaspiro[5.5]undecane-Based γ-Aminobutyric Acid Type A Receptor Antagonists with Immunomodulatory Effect.

The 3,9-diazaspiro[5.5]undecane-based compounds and have previously been reported to be potent competitive γ-aminobutyric acid type A receptor (GABAR) antagonists showing low cellular membrane permeability. Given the emerging peripheral application of GABAR ligands, we hypothesize analogs as promising lead structures for peripheral GABAR inhibition.

Molecular Determinants and Pharmacological Analysis for a Class of Competitive Non-transported Bicyclic Inhibitors of the Betaine/GABA Transporter BGT1.

The betaine/GABA transporter 1 (BGT1) is a member of the GABA transporter (GAT) family with still elusive function, largely due to a lack of potent and selective tool compounds. Based on modeling, we here present the design, synthesis and pharmacological evaluation of five novel conformationally restricted cyclic GABA analogs related to the previously reported highly potent and selective BGT1 inhibitor (1,2,5)-5-aminobicyclo[3.1.

Molecular Determinants Underlying Delta Selective Compound 2 Activity at -Containing GABA Receptors.

Delta selective compound 2 (DS2; 4-chloro--[2-(2-thienyl)imidazo[1,2-]pyridin-3-yl]benzamide) is one of the most widely used tools to study selective actions mediated by -subunit-containing GABA receptors. DS2 was discovered over 10 years ago, but despite great efforts, the precise molecular site of action has remained elusive. Using a combination of computational modeling, site-directed mutagenesis, and cell-based pharmacological assays, we probed three potential binding sites for DS2 and analogs at receptors: an interface site in the extracellular domain (ECD), equivalent to the diazepam binding site in receptors, and two sites in the transmembrane domain (TMD) - one in the and one in the interface, with the site corresponding to the binding site for etomidate and a recently disclosed low-affinity binding site for diazepam.

GABA receptor β -subunit knock-out mice show increased delta power in NREM sleep and decreased theta power in REM sleep.

γ-Aminobutyric acid (GABA) acting through heteropentameric GABA receptors plays a pivotal role in the sleep-promoting circuitry. Whereas the role of the different GABA receptor α-subunits in sleep regulation and in mediating the effect of benzodiazepines for treatment of insomnia is well-described, the β-subunits are less studied. Here we report the first study characterizing sleep in mice lacking the GABA receptor β -subunit (β mice).

Structural Determinants for the Mode of Action of Imidazopyridine DS2 at δ-Containing γ-Aminobutyric Acid Type A Receptors.

Despite the therapeutic relevance of δ-containing γ-aminobutyric acid type A receptors (GABARs) and the need for δ-selective compounds, the structural determinants for the mode and molecular site of action of δ-selective positive allosteric modulator imidazo[1,2-a]pyridine DS2 remain elusive. To guide the quest for insight, we synthesized a series of DS2 analogues guided by a structural receptor model. Using a fluorescence-based fluorometric imaging plate reader membrane potential assay, we found that the δ-selectivity and the pharmacological profile are severely affected by substituents in the 5-position of the imidazopyridine core scaffold.

Discovery of a new class of orthosteric antagonists with nanomolar potency at extrasynaptic GABA receptors.

Brain GABA receptors are ionotropic receptors belonging to the class of Cys-loop receptors and are important drug targets for the treatment of anxiety and sleep disorders. By screening a compound library (2,112 compounds) at recombinant human αβδ GABA receptors heterologously expressed in a HEK cell line, we identified a scaffold of spirocyclic compounds with nanomolar antagonist activity at GABA receptors. The initial screening hit 2027 (IC of 1.

Silencing of spontaneous activity at α4β1/3δ GABA receptors in hippocampal granule cells reveals different ligand pharmacology.

Background And Purpose: The δ-subunit-containing GABA receptors, α β δ and α β δ, in dentate gyrus granule cells (DGGCs) are known to exhibit both spontaneous channel openings (i.e. constitutive activity) and agonist-induced current.

Discovery of 2-(Imidazo[1,2- b]pyridazin-2-yl)acetic Acid as a New Class of Ligands Selective for the γ-Hydroxybutyric Acid (GHB) High-Affinity Binding Sites.

Gabazine, a γ-aminobutyric acid type A (GABA) receptor antagonist, has previously been reported to inhibit the binding of [H]NCS-382, a representative ligand of the high-affinity binding site for the neuroactive substance γ-hydroxybutyric acid (GHB). We herein report a study on the structural determinants of gabazine for binding to (i) the orthosteric binding site of the GABA receptor and (ii) the high-affinity GHB binding site. Expanding the structural diversity of available ligands for the high-affinity GHB binding sites, this study identified 2-(imidazo[1,2- b]pyridazin-2-yl)acetic acid as a novel ligand-scaffold leading to analogues with relatively high affinity ( K 0.

Molecular Hybridization of Potent and Selective γ-Hydroxybutyric Acid (GHB) Ligands: Design, Synthesis, Binding Studies, and Molecular Modeling of Novel 3-Hydroxycyclopent-1-enecarboxylic Acid (HOCPCA) and trans-γ-Hydroxycrotonic Acid (T-HCA) Analogs.

γ-Hydroxybutyric acid (GHB) is a neuroactive substance with specific high-affinity binding sites. To facilitate target identification and ligand optimization, we herein report a comprehensive structure-affinity relationship study for novel ligands targeting these binding sites. A molecular hybridization strategy was used based on the conformationally restricted 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA) and the linear GHB analog trans-4-hydroxycrotonic acid (T-HCA).

Development of a Robust Mammalian Cell-based Assay for Studying Recombinant α β δ GABA Receptor Subtypes.

δ-Containing GABA receptors are located extrasynaptically and mediate tonic inhibition. Their involvement in brain physiology positions them as interesting drug targets. There is thus a continued interest in establishing reliable recombinant expression systems for δ-containing GABA receptors.